Antiviral Compounds and Uses Thereof

ABSTRACT

This invention relates to: (a) compounds and salts thereof that, inter alia, inhibit HCV; (b) intermediates useful for the preparation of such compounds and salts; (c) compositions comprising such compounds and salts; (d) methods for preparing such intermediates, compounds, salts, and compositions; (e) methods of use of such compounds, salts, and compositions; and (f) kits comprising such compounds, salts, and compositions.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This patent application is a divisional of U.S. patent application Ser.No. 13/260,199 filed Dec. 9, 2011 which claims priority toPCT/US10/28560 filed on Mar. 25, 2010 which claims priority to U.S.Provisional Patent Application No. 61/163,155 filed Mar. 25, 2009. Theentire contents of these applications are incorporated by reference intothis patent application.

FIELD OF THE INVENTION

This invention is directed to: (a) compounds and salts thereof that,inter alia, are useful as hepatitis C virus (HCV) inhibitors; (b)intermediates useful for the preparation of such compounds and salts;(c) compositions comprising such compounds and salts; (d) methods forpreparing such intermediates, compounds, salts, and compositions; (e)methods of use of such compounds, salts, and compositions; and (f) kitscomprising such compounds, salts, and compositions.

BACKGROUND OF THE INVENTION

Hepatitis C is a blood-borne, infectious, viral disease that is causedby a hepatotropic virus called HCV. At least six different HCV genotypes(with several subtypes within each genotype) are known to date. In NorthAmerica, HCV genotype 1a predominates, followed by HCV genotypes 1b, 2a,2b, and 3a. In the United States, HCV genotypes 1, 2, and 3 are the mostcommon, with about 80% of the hepatitis C patients having HCVgenotype 1. In Europe, HCV genotype 1b is predominant, followed by HCVgenotypes 2a, 2b, 2c, and 3a. HCV genotypes 4 and 5 are found almostexclusively in Africa. As discussed below, the patient's HCV genotype isclinically important in determining the patient's potential response totherapy and the required duration of such therapy.

An HCV infection can cause liver inflammation (hepatitis) that is oftenasymptomatic, but ensuing chronic hepatitis can result in cirrhosis ofthe liver (fibrotic scarring of the liver), liver cancer, and/or liverfailure. The World Health Organization estimates that about 170 millionpersons worldwide are chronically infected with HCV, and from aboutthree to about four million persons are newly infected globally eachyear. According to the Centers for Disease Control and Prevention, aboutfour million people in the United States are infected with HCV.Co-infection with the human immunodeficiency virus (HIV) is common, andrates of HCV infection among HIV positive populations are higher.

There is a small chance of clearing the virus spontaneously, but themajority of patients with chronic hepatitis C will not clear it withouttreatment. Indications for treatment typically include proven HCVinfection and persistent abnormal liver function tests. There are twotreatment regimens that are primarily used to treat hepatitis C:monotherapy (using an interferon agent—either a “conventional” orlonger-acting pegylated interferon) and combination therapy (using aninterferon agent and ribavirin). Interferon, which is injected into thebloodstream, works by bolstering the immune response to HCV; andribavirin, which is taken orally, is believed to work by preventing HCVreplication. Taken alone, ribavirin does not effectively suppress HCVlevels, but an interferon/ribavirin combination is more effective thaninterferon alone. Typically, hepatitis C is treated with a combinationof pegylated interferon alpha and ribavirin for a period of 24 or 48weeks, depending on the HCV genotype.

The goal of treatment is sustained viral response—meaning that HCV isnot measurable in the blood after therapy is completed. Followingtreatment with a combination of pegylated interferon alpha andribavirin, sustained cure rates (sustained viral response) of about 75%or better occur in people with HCV genotypes 2 and 3 in 24 weeks oftreatment, about 50% in those with HCV genotype 1 with 48 weeks oftreatment, and about 65% in those with HCV genotype 4 in 48 weeks oftreatment.

Treatment may be physically demanding, particularly for those with priorhistory of drug or alcohol abuse, because both interferon and ribavirinhave numerous side effects. Common interferon-associated side effectsinclude flu-like symptoms, extreme fatigue, nausea, loss of appetite,thyroid problems, high blood sugar, hair loss, and skin reactions at theinjection site. Possible serious interferon-associated side effectsinclude psychoses (e.g., suicidal behavior), heart problems (e.g., heartattack, low blood pressure), other internal organ damage, blood problems(e.g., blood counts falling dangerously low), and new or worseningautoimmune disease (e.g., rheumatoid arthritis). Ribavirin-associatedside effects include anemia, fatigue, irritability, skin rash, nasalstuffiness, sinusitis, and cough. Ribavirin can also cause birthdefects, so pregnancy in female patients and female partners of malepatients must be avoided during treatment and for six months afterward.

Some patients do not complete treatment because of the serious sideeffects discussed above; other patients (non-responders) continue tohave measurable HCV levels despite treatment; and yet other patients(relapsers) “clear” the virus during therapy, but the virus returnssometime after completion of the treatment regimen. Thus, therecontinues to be a need for alternative compounds, compositions, andmethods of treatment (used either in combination with or in lieu of aninterferon agent and/or ribavirin) to alleviate the symptoms ofhepatitis C, thereby providing partial or complete relief. Thisinvention provides compounds (including salts thereof), compositions,and methods of treatment that generally address such a need.

SUMMARY OF THE INVENTION

This invention is directed to compounds that correspond in structure toformula (I):

In formula (I):

-   -   R¹ is selected from the group consisting of:

arylcarbonyl, and heteroarylcarbonyl;

is selected from the group consisting of single carbon-carbon bond anddouble carbon-carbon bond;

R⁵, R⁶, R⁸, R¹¹, R¹², R¹³, and R¹⁴ are independently selected from thegroup consisting of hydrogen, methyl, and nitrogen-protecting group;

R⁷ is selected from the group consisting of hydrogen and methyl;

R⁹ is halo;

R¹⁰ is halo;

n is selected from the group consisting of 1, 2, and 3;

R¹⁵ is selected from the group consisting of hydrogen, amino, andnitrogen-protecting group substituted amino;

m is selected from the group consisting of 0, 1, 2, and 3;

R¹⁶ is selected from the group consisting of hydrogen, aryl, alkyl, andalkyloxycarbonyl;

R² is selected from the group consisting of halo, alkyl, alkenyl,alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino,aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, andheterocyclyl, wherein:

-   -   (a) the amino, aminocarbonyl, and aminosulfonyl optionally are        substituted with:        -   (1) one or two substituents independently selected from the            group consisting of alkyl, alkenyl, alkynyl, and            alkylsulfonyl, or        -   (2) two substituents that, together with the amino nitrogen,            form a single-ring heterocyclyl, and    -   (b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy,        alkynyloxy, and alkylsulfonyl, optionally are substituted with        one or more substituents independently selected from the group        consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino,        alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl,        wherein:        -   the amino optionally is substituted with:            -   (1) one or two substituents independently selected from                the group consisting of alkyl, alkenyl, alkynyl,                alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl,                carbocyclyl, heterocyclyl, carbocyclylalkyl, and                heterocyclylalkyl, or            -   (2) two substituents that, together with the amino                nitrogen, form a single-ring heterocyclyl, and    -   (c) the carbocyclyl and heterocyclyl optionally are substituted        with up to three substituents independently selected from the        group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro,        cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl,        carbocyclyl, and heterocyclyl, wherein:        -   the amino optionally is substituted with:            -   (1) one or two substituents independently selected from                the group consisting of alkyl, alkenyl, alkynyl,                alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl,                carbocyclyl, heterocyclyl, carbocyclylalkyl, and                heterocyclylalkyl, or            -   (2) two substituents that, together with the amino                nitrogen, form a single-ring heterocyclyl;

R³ is selected from the group consisting of hydrogen, hydroxy, alkyl,alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy,amino, carbocyclylsulfonyloxy, haloalkylsulfonyloxy, and halo;

as to L and R⁴:

-   -   L is a bond, and R⁴ is selected from the group consisting of        C₅-C₆-carbocyclyl, fused 2-ring carbocyclyl and fused 2-ring        heterocyclyl, wherein each such substituent optionally is        substituted with one or more substituents independently selected        from the group consisting of R^(E), R^(F), R^(G), R^(H), R^(I),        R^(J), and R^(K), or    -   L is selected from the group consisting of C(R^(A))═C(R^(B)),        C≡C, C(O)N(R^(C)), N(R^(D))C(O), C₁-C₂-alkylene, CH₂O, OCH₂,        cyclopropyl-1,2-ene, CH₂N(R^(L)), N(R^(M))CH₂, C(O)CH₂, and        CH₂C(O), and R⁴ is selected from the group consisting of        C₅-C₆-carbocyclyl and 5-6-membered heterocyclyl, wherein each        such substituent optionally is substituted with one or more        substituents independently selected from the group consisting of        R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K);

R^(A), R^(B), R^(L), and R^(M) are independently selected from the groupconsisting of hydrogen, C₁-C₆-alkyl, C₁-C₆-alkyloxy, C₃-C₈-cycloalkyl,and halo, wherein:

-   -   the C₁-C₆-alkyl optionally is substituted with one or more        substituents independently selected from the group consisting of        carboxy, halo, hydroxy, nitro, oxo, amino, cyano,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, and        heterocyclyl;

R^(C) is selected from the group consisting of hydrogen and alkyl;

R^(D) is selected from the group consisting of hydrogen and alkyl;

each R^(E) is independently selected from the group consisting of halo,nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido, and aldehydro,wherein:

-   -   the amino optionally is substituted with one or two substituents        independently selected from the group consisting of alkyl,        alkenyl, and alkynyl;

each R^(E) is independently selected from the group consisting of alkyl,alkenyl, and alkynyl, wherein:

-   -   each such substituent optionally is substituted with one or more        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo,        aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl,        alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,        alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy,        alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl,        wherein:        -   the amino, imino, aminosulfonyl, aminocarbonyl, carbocyclyl,            and heterocyclyl optionally are substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl,            alkenylsulfonyl, alkynylsulfonyl, alkylsulfonylamino,            hydroxy, and alkyloxy, wherein:            -   amino portion of the alkylsulfonylamino optionally is                substituted with a substituent selected from the group                consisting of alkyl, alkenyl, and alkynyl;

each R^(G) is independently selected from the group consisting ofcarbocyclyl and heterocyclyl, wherein:

-   -   each such substituent optionally is substituted with one or more        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, carboxy, hydroxy, halo, amino, nitro,        azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,        alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy,        alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy,        carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl,            alkynyl, alkylsulfonyl, alkenylsulfonyl, and            alkynylsulfonyl;

each R^(H) is independently selected from the group consisting ofalkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy,and alkynylsulfonyloxy, wherein:

-   -   each such substituent optionally is substituted with one or more        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,        alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy,        alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl,        cyano, and aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl,            alkynyl, alkylsulfonyl, alkenylsulfonyl, and            alkynylsulfonyl;

each R^(I) is independently selected from the group consisting ofalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl,alkyloxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl,wherein:

-   -   (a) the alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl        optionally are substituted with one or more substituents        independently selected from the group consisting of carboxy,        hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,        alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy,        alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl,        cyano, and aminocarbonyl, and    -   (b) the aminocarbonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, alkyloxyalkyl, carbocyclyl,        heterocyclyl, alkylsulfonyl, and alkylsulfonylamino, wherein:        -   the carbocyclyl and heterocyclyl optionally are substituted            with one or two substituents independently selected from the            group consisting of halo, alkyl, and oxo;

each R^(J) is independently selected from the group consisting ofcarbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino,alkenylcarbonylamino, alkynylcarbonylamino, alkyloxycarbonylamino,alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino,alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino,alkyloxycarbonylaminoimino, alkylsulfonylaminoimino,alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein:

-   -   (a) the amino portion of such substituents optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl,        alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or more substituents independently            selected from the group consisting of alkyl, alkenyl,            alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy,            halo, nitro, cyano, azido, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl,    -   (b) the alkyl, alkenyl, and alkynyl portion of such substituents        optionally is substituted with one or more substituents        independently selected from the group consisting of carboxy,        halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy,        alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy,            and alkynyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy;    -   (c) the carbocyclyl and heterocyclyl portions of such        substituents optionally are substituted with one or more        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy,        alkynyloxy, halo, nitro, cyano, azido, and amino, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, and alkynyl; and

each R^(K) is independently selected from the group consisting of aminosulfonyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl, wherein:

-   -   (a) the alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl        optionally are substituted with one or more substituents        independently selected from the group consisting of carboxy,        hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,        alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy,        alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl,        cyano, and aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl; and    -   (b) the aminosulfonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl, alkenyl, and alkynyl.

This invention also is directed to the salts (including pharmaceuticallyacceptable salts) of the compounds of the invention.

This invention also is directed to compositions (includingpharmaceutical compositions) that comprise one or more compounds and/orsalts of the invention, and, optionally, one or more additionaltherapeutic agents.

This invention also is directed to kits that comprise one or morecompounds and/or salts of the invention, and, optionally, one or moreadditional therapeutic agents.

This invention also is directed to methods of use of the compounds,salts, compositions, and/or kits of the invention to, for example,inhibit replication of an RNA virus (including HCV), treat a diseasetreatable by inhibiting HCV ribonucleic acid (RNA) polymerase (includinghepatitis C).

This invention also is directed to a use of one or more compounds and/orsalts of the invention to prepare a medicament. The medicamentoptionally can comprise one or more additional therapeutic agents. Insome embodiments, the medicament is useful for treating hepatitis C.

Further benefits of Applicants' invention will be apparent to oneskilled in the art from reading this patent application.

DETAILED DESCRIPTION OF THE INVENTION

This detailed description is intended only to acquaint others skilled inthe art with Applicants' invention, its principles, and its practicalapplication so that others skilled in the art may adapt and apply theinvention in its numerous forms, as they may be best suited to therequirements of a particular use. This description and its specificexamples are intended for purposes of illustration only. This invention,therefore, is not limited to the embodiments described in this patentapplication, and may be variously modified.

A. DEFINITIONS

The term “alkyl” (alone or in combination with another term(s)) means astraight-or branched-chain saturated hydrocarbyl substituent typicallycontaining from 1 to about 20 carbon atoms, more typically from 1 toabout 8 carbon atoms, and even more typically from 1 to about 6 carbonatoms. Examples of such substituents include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,and hexyl. As in this definition, throughout this detailed descriptionApplicants have provided illustrative examples. The provision of suchillustrative examples should not be interpreted as if the providedillustrative examples are the only options available to one skilled inthe art.

The term “alkenyl” (alone or in combination with another term(s)) meansa straight- or branched-chain hydrocarbyl substituent containing one ormore double bonds and typically from 2 to about 20 carbon atoms, moretypically from about 2 to about 8 carbon atoms, and even more typicallyfrom about 2 to about 6 carbon atoms. Examples of such substituentsinclude ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl,1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl.

The term “alkynyl” (alone or in combination with another term(s)) meansa straight- or branched-chain hydrocarbyl substituent containing one ormore triple bonds and typically from 2 to about 20 carbon atoms, moretypically from about 2 to about 8 carbon atoms, and even more typicallyfrom about 2 to about 6 carbon atoms. Examples of such substituentsinclude ethynyl, 2-propynyl, 3-propynyl, 2-butynyl, and 3-butynyl.

The term “carbocyclyl” (alone or in combination with another term(s))means a saturated cyclic (i.e., “cycloalkyl”), partially saturatedcyclic (i.e., “cycloalkenyl”), or completely unsaturated (i.e., “aryl”)hydrocarbyl substituent containing from 3 to 14 carbon ring atoms (“ringatoms” are the atoms bound together to form the ring or rings of acyclic substituent). A carbocyclyl may be a single ring, which typicallycontains from 3 to 6 ring atoms. Examples of such single-ringcarbocyclyls include cyclopropyl (cyclopropanyl), cyclobutyl(cyclobutanyl), cyclopentyl (cyclopentanyl), cyclopentenyl,cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl,cyclohexadienyl, and phenyl. A carbocyclyl alternatively may be 2 or 3rings fused together, such as naphthalenyl, tetrahydronaphthalenyl(tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl,phenanthrenyl, and decalinyl.

The term “cycloalkyl” (alone or in combination with another term(s))means a saturated cyclic hydrocarbyl substituent containing from 3 to 14carbon ring atoms. A cycloalkyl may be a single carbon ring, whichtypically contains from 3 to 6 carbon ring atoms. Examples ofsingle-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,and cyclohexyl. A cycloalkyl alternatively may be 2 or 3 carbon ringsfused together, such as, decalinyl.

The term “aryl” (alone or in combination with another term(s)) means anaromatic carbocyclyl containing from 6 to 14 carbon ring atoms. Examplesof aryls include phenyl, naphthalenyl, and indenyl.

In some instances, the number of carbon atoms in a hydrocarbylsubstituent (e.g., alkyl, alkenyl, alkynyl, or cycloalkyl) is indicatedby the prefix “C_(x)-C_(y)—”, wherein x is the minimum and y is themaximum number of carbon atoms in the substituent. Thus, for example,“C₁-C₆-alkyl” refers to an alkyl substituent containing from 1 to 6carbon atoms. Illustrating further, C₃-C₆-cycloalkyl means a saturatedhydrocarbyl ring containing from 3 to 6 carbon ring atoms.

The term “hydrogen” (alone or in combination with another term(s)) meansa hydrogen radical, and may be depicted as —H.

The term “hydroxy” (alone or in combination with another term(s)) means—OH.

The term “nitro” (alone or in combination with another term(s)) means—NO₂.

The term “cyano” (alone or in combination with another term(s)) means—CN, which also may be depicted as —C≡N.

The term “keto” (alone or in combination with another term(s)) means anoxo radical, and may be depicted as ═O.

The term “carboxy” (alone or in combination with another term(s)) means—C(O)—OH.

The term “amino” (alone or in combination with another term(s)) means—NH₂.

The term “imino” (alone or in combination with another term(s)) means═NH.

The term “aminoimino” (alone or in combination with another term(s))means ═NNH₂.

The term “halogen” or “halo” (alone or in combination with anotherterm(s)) means a fluorine radical (which may be depicted as —F),chlorine radical (which may be depicted as —Cl), bromine radical (whichmay be depicted as —Br), or iodine radical (which may be depicted as—I).

A substituent is “substitutable” if it comprises at least one carbon ornitrogen atom that is bonded to one or more hydrogen atoms. Thus, forexample, hydrogen, halogen, and cyano do not fall within thisdefinition. In addition, a sulfur atom in a heterocyclyl containing suchatom is substitutable with one or two oxo substituents.

If a substituent is described as being “substituted”, a non-hydrogenradical is in the place of hydrogen radical on a carbon or nitrogen ofthe substituent. Thus, for example, a substituted alkyl substituent isan alkyl substituent in which at least one non-hydrogen radical is inthe place of a hydrogen radical on the alkyl substituent. To illustrate,monofluoroalkyl is alkyl substituted with a fluoro radical, anddifluoroalkyl is alkyl substituted with two fluoro radicals. It shouldbe recognized that if there are more than one substitution on asubstituent, each non-hydrogen radical may be identical or different(unless otherwise stated).

If a substituent is described as being “optionally substituted”, thesubstituent may be either (1) not substituted or (2) substituted. If asubstituent is described as being optionally substituted with up to aparticular number of non-hydrogen radicals, that substituent may beeither (1) not substituted; or (2) substituted by up to that particularnumber of non-hydrogen radicals or by up to the maximum number ofsubstitutable positions on the substituent, whichever is less. Thus, forexample, if a substituent is described as a heteroaryl optionallysubstituted with up to 3 non-hydrogen radicals, then any heteroaryl withless than 3 substitutable positions would be optionally substituted byup to only as many non-hydrogen radicals as the heteroaryl hassubstitutable positions. To illustrate, tetrazolyl (which has only onesubstitutable position) would be optionally substituted with up to onenon-hydrogen radical. To illustrate further, if an amino nitrogen isdescribed as being optionally substituted with up to 2 non-hydrogenradicals, then a primary amino nitrogen will be optionally substitutedwith up to 2 non-hydrogen radicals, whereas a secondary amino nitrogenwill be optionally substituted with up to only 1 non-hydrogen radical.

This patent application uses the terms “substituent” and “radical”interchangeably.

The prefix “halo” indicates that the substituent to which the prefix isattached is substituted with one or more independently selected halogenradicals. For example, haloalkyl means an alkyl substituent in which atleast one hydrogen radical is replaced with a halogen radical. Examplesof haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. It should berecognized that if a substituent is substituted by more than one halogenradical, those halogen radicals may be identical or different (unlessotherwise stated).

The prefix “perhalo” indicates that every hydrogen radical on thesubstituent to which the prefix is attached is replaced withindependently selected halogen radicals, i.e., each hydrogen radical onthe substituent is replaced with a halogen radical. If all the halogenradicals are identical, the prefix typically will identify the halogenradical. Thus, for example, the term “perfluoro” means that everyhydrogen radical on the substituent to which the prefix is attached issubstituted with a fluorine radical. To illustrate, the term“perfluoroalkyl” means an alkyl substituent wherein a fluorine radicalis in the place of each hydrogen radical.

The term “carbonyl” (alone or in combination with another term(s)) means—C(O)—.

The term “aminocarbonyl” (alone or in combination with another term(s))means —C(O)—NH₂.

The term “oxy” (alone or in combination with another term(s)) means anether substituent, and may be depicted as —O—.

The term “alkyloxy” or “alkoxy” (alone or in combination with anotherterm(s)) means an alkylether substituent, i.e., —O-alkyl. Examples ofsuch a substituent include methoxy (—O—CH₃), ethoxy, n-propoxy,isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

The term “alkylcarbonyl” (alone or in combination with another term(s))means —C(O)-alkyl.

The term “aminoalkylcarbonyl” (alone or in combination with anotherterm(s)) means —C(O)-alkyl-NH₂.

The term “alkyloxycarbonyl” (alone or in combination with anotherterm(s)) means —C(O)—O-alkyl.

The term “carbocyclylcarbonyl” (alone or in combination with anotherterm(s)) means —C(O)-carbocyclyl.

Similarly, the term “heterocyclylcarbonyl” (alone or in combination withanother term(s)) means —C(O)-heterocyclyl.

The term “carbocyclylalkylcarbonyl” (alone or in combination withanother term(s)) means —C(O)-alkyl-carbocyclyl.

Similarly, the term “heterocyclylalkylcarbonyl” (alone or in combinationwith another term(s)) means —C(O)-alkyl-heterocyclyl.

The term “carbocyclyloxycarbonyl” (alone or in combination with anotherterm(s)) means —C(O)—O-carbocyclyl.

The term “carbocyclylalkyloxycarbonyl” (alone or in combination withanother term(s)) means —C(O)—O-alkyl-carbocyclyl.

The term “thio” or “thia” (alone or in combination with another term(s))means a thiaether substituent, i.e., an ether substituent wherein adivalent sulfur atom is in the place of the ether oxygen atom. Such asubstituent may be depicted as —S—. This, for example,“alkyl-thio-alkyl” means alkyl-S-alkyl (alkyl-sulfanyl-alkyl).

The term “thiol” or “sulfhydryl” (alone or in combination with anotherterm(s)) means a sulfhydryl substituent, and may be depicted as —SH.

The term “(thiocarbonyl)” (alone or in combination with another term(s))means a carbonyl wherein the oxygen atom has been replaced with asulfur. Such a substituent may be depicted as —C(S)—.

The term “sulfonyl” (alone or in combination with another term(s)) means—S(O)₂—.

The term “aminosulfonyl” (alone or in combination with another term(s))means —S(O)₂—NH₂.

The term “sulfinyl” or “sulfoxido” (alone or in combination with anotherterm(s)) means —S(O)—.

The term “heterocyclyl” (alone or in combination with another term(s))means a saturated (i.e., “heterocycloalkyl”), partially saturated (i.e.,“heterocycloalkenyl”), or completely unsaturated (i.e., “heteroaryl”)ring structure containing a total of 3 to 14 ring atoms. At least one ofthe ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), withthe remaining ring atoms being independently selected from the groupconsisting of carbon, oxygen, nitrogen, and sulfur.

A heterocyclyl may be a single ring, which typically contains from 3 to7 ring atoms, more typically from 3 to 6 ring atoms, and even moretypically 5 to 6 ring atoms. Examples of single-ring heterocyclylsinclude furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl(thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl,pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl,pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl,oxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl,thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl,thiodiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (furazanyl), or 1,3,4-oxadiazolyl),oxatriazolyl (including 1,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl),dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl,1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), oxathiazolyl, oxathiolyl,oxathiolanyl, pyranyl, dihydropyranyl, thiopyranyl,tetrahydrothiopyranyl, pyridinyl (azinyl), piperidinyl, diazinyl(including pyridazinyl (1,2-diazinyl), pyrimidinyl (1,3-diazinyl), orpyrazinyl (1,4-diazinyl)), piperazinyl, triazinyl (including1,3,5-triazinyl, 1,2,4-triazinyl, and 1,2,3-triazinyl)), oxazinyl(including 1,2-oxazinyl, 1,3-oxazinyl, or 1,4-oxazinyl)), oxathiazinyl(including 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl,or 1,2,6-oxathiazinyl)), oxadiazinyl (including 1,2,3-oxadiazinyl,1,2,4-oxadiazinyl, 1,4,2-oxadiazinyl, or 1,3,5-oxadiazinyl)),morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.

A heterocyclyl alternatively may be 2 or 3 rings fused together, suchas, for example, indolizinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl,naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl,pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl.Other examples of fused-ring heterocyclyls include benzo-fusedheterocyclyls, such as indolyl, isoindolyl (isobenzazolyl,pseudoisoindolyl), indoleninyl (pseudoindolyl), isoindazolyl(benzpyrazolyl), benzazinyl (including quinolinyl (1-benzazinyl) orisoquinolinyl (2-benzazinyl)), phthalazinyl, quinoxalinyl, quinazolinyl,benzodiazinyl (including cinnolinyl (1,2-benzodiazinyl) or quinazolinyl(1,3-benzodiazinyl)), benzopyranyl (including chromanyl orisochromanyl), benzoxazinyl (including 1,3,2-benzoxazinyl,1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, or 3,1,4-benzoxazinyl), andbenzisoxazinyl (including 1,2-benzisoxazinyl or 1,4-benzisoxazinyl).

The term “2-fused ring” heterocyclyl (alone or in combination withanother term(s)) means a saturated, partially saturated, or arylheterocyclyl containing 2 fused rings. Examples of 2-fused-ringheterocyclyls include indolizinyl, quinolizinyl, purinyl,naphthyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl,isoindazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl,benzopyranyl, benzothiopyranyl, benzoxazolyl, anthranilyl,benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl,isobenzofuranyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl,benzotriazolyl, benzoxazinyl, and tetrahydroisoquinolinyl.

The term “heteroaryl” (alone or in combination with another term(s))means an aromatic heterocyclyl containing from 5 to 14 ring atoms. Aheteroaryl may be a single ring or 2 or 3 fused rings. Examples ofheteroaryl substituents include 6-membered ring substituents such aspyridyl, pyrazyl, pyrimidinyl, pyridazinyl, and 1,3,5-, 1,2,4- or1,2,3-triazinyl; 5-membered ring substituents such as imidazyl, furanyl,thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-,1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ringsubstituents such as benzothiofuranyl, benzisoxazolyl, benzoxazolyl,purinyl, and anthranilyl; and 6/6-membered fused rings such asbenzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, andbenzoxazinyl.

A prefix attached to a multi-component substituent only applies to thefirst component. To illustrate, the term “alkylcycloalkyl” contains twocomponents: alkyl and cycloalkyl. Thus, the C₁-C₆-prefix onC₁-C₆-alkylcycloalkyl means that the alkyl component of thealkylcycloalkyl contains from 1 to 6 carbon atoms; the C₁-C₆-prefix doesnot describe the cycloalkyl component. To illustrate further, the prefix“halo” on haloalkoxyalkyl indicates that only the alkoxy component ofthe alkoxyalkyl substituent is substituted with one or more halogenradicals. If halogen substitution may alternatively or additionallyoccur on the alkyl component, the substituent would instead be describedas “halogen-substituted alkoxyalkyl” rather than “haloalkoxyalkyl.” Andfinally, if the halogen substitution may only occur on the alkylcomponent, the substituent would instead be described as“alkoxyhaloalkyl.”

If substituents are described as being “independently selected” from agroup, each substituent is selected independent of the other. Eachsubstituent therefore may be identical to or different from the othersubstituent(s).

When words are used to describe a substituent, the rightmost-describedcomponent of the substituent is the component that has the free valence.

When a chemical formula is used to describe a substituent, the dash onthe left side of the formula indicates the portion of the substituentthat has the free valence.

When a chemical formula is used to describe a linking element betweentwo other elements of a depicted chemical structure, the leftmost dashof the substituent indicates the portion of the substituent that isbound to the left element in the depicted structure. The rightmost dash,on the other hand, indicates the portion of the substituent that isbound to the right element in the depicted structure. To illustrate, ifthe depicted chemical structure is X-L-Y and L is described as—C(O)—NH—, then the chemical would be X—C(O)—NH—Y.

With reference to the use of the words “comprise” or “comprises” or“comprising” in this patent application (including the claims),Applicants note that unless the context requires otherwise, those wordsare used on the basis and clear understanding that they are to beinterpreted inclusively, rather than exclusively, and that Applicantsintend each of those words to be so interpreted in construing thispatent application, including the claims below.

ChemDraw software has been used to generate the compound names in thispatent application.

The term “purity”, unless otherwise qualified, means the chemical purityof a compound according to conventional HPLC assay.

B. COMPOUNDS

As discussed above, this invention is directed, in part, to compoundsthat correspond in structure to formula (I):

B1. Substituents R¹

In some embodiments, R¹ is:

In these embodiments, the compounds correspond in structure to formulaI-1:

In some such embodiments, R¹ is:

In these embodiments, the compounds correspond in structure to formulaI-1A:

In other such embodiments, R¹ is:

In these embodiments, the compounds correspond in structure to formulaI-1B:

In some embodiments, R¹ is:

In these embodiments, the compounds correspond in structure to formulaI-2:

In some embodiments, R¹ is:

In these embodiments, the compounds correspond in structure to formulaI-3:

In some embodiments, R¹ is:

In these embodiments, the compounds correspond in structure to formulaI-4:

In some embodiments, R¹ is:

In these embodiments, the compounds correspond in structure to formulaI-5:

In some embodiments, R¹ is:

In these embodiments, the compounds correspond in structure to formulaI-6:

In some embodiments, R¹ is:

In these embodiments, the compounds correspond in structure to formulaI-7:

In some embodiments, R¹ is:

In these embodiments, the compounds correspond in structure to formulaI-8:

In some embodiments, R¹ is:

In these embodiments, the compounds correspond in structure to formulaI-9:

In some embodiments, R¹ is:

In these embodiments, the compounds correspond in structure to formulaI-10:

In some embodiments, R¹ is:

In these embodiments, the compounds correspond in structure to formulaI-11:

In some embodiments, R¹ is:

In these embodiments, the compounds correspond in structure to formulaI-12:

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is arylcarbonyl. In some such embodiments, R¹ isphenylcarbonyl.

In some embodiments, R¹ is heteroarylcarbonyl.

B2. Substituents R⁵

R⁵ is selected from the group consisting of hydrogen, methyl, andnitrogen-protecting group.

In some embodiments, R⁵ is hydrogen.

In some embodiments, R⁵ is methyl.

In some embodiments, R⁵ is selected from the group consisting ofhydrogen and methyl.

In some embodiments, R⁵ is a nitrogen-protecting group. In theseembodiments, the compounds are useful as intermediates for thepreparation of compounds of formula (I). Nitrogen-protecting groupssuitable for preparing compounds of formula (I) are known to thoseskilled in the art.

B3. Substituents R⁶

R⁶ is selected from the group consisting of hydrogen, methyl, andnitrogen-protecting group.

In some embodiments, R⁶ is hydrogen.

In some embodiments, R⁶ is methyl.

In some embodiments, R⁶ is selected from the group consisting ofhydrogen and methyl.

In some embodiments, R⁶ is a nitrogen-protecting group. In theseembodiments, the compounds are useful as intermediates for thepreparation of compounds of formula (I). Nitrogen-protecting groupssuitable for preparing compounds of formula (I) are known to thoseskilled in the art.

B4. Substituents R⁷

R⁷ is selected from the group consisting of hydrogen and methyl.

In some embodiments, R⁷ is hydrogen.

In some embodiments, R⁷ is methyl.

B5. Substituents R⁸

R⁸ is selected from the group consisting of hydrogen, methyl, andnitrogen-protecting group.

In some embodiments, R⁸ is hydrogen.

In some embodiments, R⁸ is methyl.

In some embodiments, R⁸ is selected from the group consisting ofhydrogen and methyl.

In some embodiments, R⁸ is a nitrogen-protecting group. In theseembodiments, the compounds are useful as intermediates for thepreparation of compounds of formula (I). Nitrogen-protecting groupssuitable for preparing compounds of formula (I) are known to thoseskilled in the art.

B6. Substituents R⁹

R⁹ is halo. In some such embodiments, R⁹ is fluoro.

B7. Substituents R¹⁰

R¹⁰ is halo. In some such embodiments, R¹⁰ is fluoro.

B8. Substituents R¹¹

R¹¹ is selected from the group consisting of hydrogen, methyl, andnitrogen-protecting group.

In some embodiments, R¹¹ is hydrogen.

In some embodiments, R¹¹ is methyl.

In some embodiments, R¹¹ is selected from the group consisting ofhydrogen and methyl.

In some embodiments, R¹¹ is a nitrogen-protecting group. In theseembodiments, the compounds are useful as intermediates for thepreparation of compounds of formula (I). Nitrogen-protecting groupssuitable for preparing compounds of formula (I) are known to thoseskilled in the art.

B9. Substituents R¹²

R¹² is selected from the group consisting of hydrogen, methyl, andnitrogen-protecting group.

In some embodiments, R¹² is hydrogen.

In some embodiments, R¹² is methyl.

In some embodiments, R¹² is selected from the group consisting ofhydrogen and methyl.

In some embodiments, R¹² is a nitrogen-protecting group. In theseembodiments, the compounds are useful as intermediates for thepreparation of compounds of formula (I). Nitrogen-protecting groupssuitable for preparing compounds of formula (I) are known to thoseskilled in the art.

B10. Substituents R¹³

R¹³ is selected from the group consisting of hydrogen, methyl, andnitrogen-protecting group.

In some embodiments, R¹³ is hydrogen.

In some embodiments, R¹³ is methyl.

In some embodiments, R¹³ is selected from the group consisting ofhydrogen and methyl.

In some embodiments, R¹³ is a nitrogen-protecting group. In theseembodiments, the compounds are useful as intermediates for thepreparation of compounds of formula (I). Nitrogen-protecting groupssuitable for preparing compounds of formula (I) are known to thoseskilled in the art.

B11. Substituents R¹⁴

R¹⁴ is selected from the group consisting of hydrogen, methyl, andnitrogen-protecting group.

In some embodiments, R¹⁴ is hydrogen.

In some embodiments, R¹⁴ is methyl.

In some embodiments, R¹⁴ is selected from the group consisting ofhydrogen and methyl.

In some embodiments, R¹⁴ is a nitrogen-protecting group. In theseembodiments, the compounds are useful as intermediates for thepreparation of compounds of formula (I). Nitrogen-protecting groupssuitable for preparing compounds of formula (I) are known to thoseskilled in the art.

B12. Substituents R¹⁵

R¹⁵ is selected from the group consisting of hydrogen, amino, andnitrogen-protecting group substituted amino.

In some embodiments, R¹⁵ is hydrogen.

In some embodiments, R¹⁵ is amino.

In some embodiments, R¹⁵ is a nitrogen-protecting group substitutedamino. Nitrogen-protecting groups suitable for preparing compounds offormula (I) are known to those skilled in the art.

B13. Substituents R¹⁶

R¹⁶ is selected from the group consisting of hydrogen, aryl, alkyl, andalkyloxycarbonyl.

In some embodiments, R¹⁶ is hydrogen.

In some embodiments, R¹⁶ is aryl.

In some embodiments, R¹⁶ is alkyl.

In some embodiments, R¹⁶ is alkyloxycarbonyl.

B14. Substituent R²

R² is selected from the group consisting of halo, alkyl, alkenyl,alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy, alkynyloxy, amino,aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocyclyl, andheterocyclyl, wherein:

-   -   (a) the amino, aminocarbonyl, and aminosulfonyl optionally are        substituted with:        -   (1) one or two substituents independently selected from the            group consisting of alkyl, alkenyl, alkynyl, and            alkylsulfonyl, or        -   (2) two substituents that, together with the amino nitrogen,            form a single-ring heterocyclyl,    -   (b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy,        alkynyloxy, and alkylsulfonyl, optionally are substituted with        one or more substituents independently selected from the group        consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino,        alkyloxy, trimethylsilyl, carbocyclyl, and heterocyclyl,        wherein:        -   the amino optionally is substituted with:            -   (1) one or two substituents independently selected from                the group consisting of alkyl, alkenyl, alkynyl,                alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl,                carbocyclyl, heterocyclyl, carbocyclylalkyl, and                heterocyclylalkyl, or            -   (2) two substituents that, together with the amino                nitrogen, form a single-ring heterocyclyl, and    -   (c) the carbocyclyl and heterocyclyl optionally are substituted        with up to three substituents independently selected from the        group consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro,        cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl,        carbocyclyl, and heterocyclyl, wherein:        -   the amino optionally is substituted with:            -   (1) one or two substituents independently selected from                the group consisting of alkyl, alkenyl, alkynyl,                alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl,                carbocyclyl, heterocyclyl, carbocyclylalkyl, and                heterocyclylalkyl, or            -   (2) two substituents that, together with the amino                nitrogen, form a single-ring heterocyclyl.

In some embodiments, R² is selected from the group consisting of halo,alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy,alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl,carbocyclyl, and heterocyclyl, wherein:

-   -   the amino, aminocarbonyl, and aminosulfonyl optionally are        substituted with:        -   (1) one or two substituents independently selected from the            group consisting of alkyl, alkenyl, alkynyl, and            alkylsulfonyl, or        -   (2) two substituents that, together with the amino nitrogen,            form a single-ring heterocyclyl.

In some embodiments, R² is selected from the group consisting of halo,alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy,alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl,carbocyclyl, and heterocyclyl, wherein:

-   -   the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy,        and alkylsulfonyl, optionally are substituted with one or more        substituents independently selected from the group consisting of        halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy,        trimethylsilyl, carbocyclyl, and heterocyclyl, wherein:    -   the amino optionally is substituted with:        -   (1) one or two substituents independently selected from the            group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl,            alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl,            carbocyclylalkyl, and heterocyclylalkyl, or        -   (2) two substituents that, together with the amino nitrogen,            form a single-ring heterocyclyl.

In some embodiments, R² is selected from the group consisting of halo,alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy,alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl,carbocyclyl, and heterocyclyl, wherein:

-   -   the carbocyclyl and heterocyclyl optionally are substituted with        up to three substituents independently selected from the group        consisting of alkyl, alkenyl, alkynyl, halo, oxo, nitro, cyano,        azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl,        and heterocyclyl, wherein:        -   the amino optionally is substituted with:            -   (1) one or two substituents independently selected from                the group consisting of alkyl, alkenyl, alkynyl,                alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl,                carbocyclyl, heterocyclyl, carbocyclylalkyl, and                heterocyclylalkyl, or            -   (2) two substituents that, together with the amino                nitrogen, form a single-ring heterocyclyl.

In some embodiments, R² is selected from the group consisting of halo,alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy,alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl,carbocyclyl, and heterocyclyl, wherein:

-   -   (a) the amino, aminocarbonyl, and aminosulfonyl optionally are        substituted with:        -   (1) one or two substituents independently selected from the            group consisting of alkyl, alkenyl, and alkynyl, or,        -   (2) two substituents that, together with the amino nitrogen,            form a single-ring heterocyclyl; and    -   (b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy,        alkynyloxy, alkylsulfonyl, carbocyclyl, and heterocyclyl        optionally are substituted with up to three substituents        independently selected from the group consisting of halo, oxo,        nitro, cyano, azido, hydroxy, amino, alkyloxy, carbocyclyl, and        heterocyclyl, wherein the amino optionally is substituted with:        -   (1) one or two substituents independently selected from the            group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl,            alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl,            carbocyclylalkyl, and heterocyclylalkyl, or,        -   (2) two substituents that, together with the amino nitrogen,            form a single-ring heterocyclyl.

In some embodiments, R² is selected from the group consisting of halo,alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy,alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl,carbocyclyl, and heterocyclyl, wherein:

the amino, aminocarbonyl, and aminosulfonyl optionally are substitutedwith:

-   -   (1) one or two substituents independently selected from the        group consisting of alkyl, alkenyl, and alkynyl, or,    -   (2) two substituents that, together with the amino nitrogen,        form a single-ring heterocyclyl.

In some embodiments, R² is selected from the group consisting of halo,alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy,alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl,carbocyclyl, and heterocyclyl, wherein:

the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy,alkylsulfonyl, carbocyclyl, and heterocyclyl optionally are substitutedwith up to three substituents independently selected from the groupconsisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy,carbocyclyl, and heterocyclyl, wherein the amino optionally issubstituted with:

-   -   (1) one or two substituents independently selected from the        group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl,        alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl,        carbocyclylalkyl, and heterocyclylalkyl, or,    -   (2) two substituents that, together with the amino nitrogen,        form a single-ring heterocyclyl.

In some embodiments, R² is selected from the group consisting of halo,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl,C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:

-   -   (a) the amino optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, and alkylsulfonyl,    -   (b) the C₁-C₄-alkyl, C₂-C₄-alkenyl, and C₂-C₄-alkynyl optionally        are substituted with one or more substituents independently        selected from the group consisting of halo, oxo, hydroxy,        alkyloxy, and trimethylsilyl, and    -   (c) the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl        optionally are substituted with up to three substituents        independently selected from the group consisting of alkyl,        alkenyl, alkynyl, halo, and amino, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl.

In some embodiments, R² is selected from the group consisting ofC₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl,C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:

-   -   (a) the amino optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, and alkylsulfonyl,    -   (b) the C₁-C₄-alkyl, C₂-C₄-alkenyl, and C₂-C₄-alkynyl optionally        are substituted with one or more substituents independently        selected from the group consisting of halo, oxo, hydroxy,        alkyloxy, and trimethylsilyl, and    -   (c) the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl        optionally are substituted with up to three substituents        independently selected from the group consisting of alkyl,        alkenyl, alkynyl, halo, and amino, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, alkynyl, and alkylsulfonyl.

In some embodiments, R² is selected from the group consisting of halo,C₁-C₄-alkyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:

-   -   (a) the C₁-C₄-alkyl optionally is substituted with up to three        substituents independently selected from the group consisting of        halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and    -   (b) the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl        optionally are substituted with one or two substituents        independently selected from the group consisting of alkyl, halo,        and alkylsulfonylamino.

In some embodiments, R² is selected from the group consisting of halo,C₁-C₄-alkyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:

-   -   (a) the C₁-C₄-alkyl optionally is substituted with one or two        substituents independently selected from the group consisting of        halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and    -   (b) the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl        optionally are substituted with a substituent selected from the        group consisting of alkyl, halo, and alkylsulfonylamino.

In some embodiments, R² is selected from the group consisting ofC₁-C₄-alkyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:

-   -   (a) the C₁-C₄-alkyl optionally is substituted with up to three        substituents independently selected from the group consisting of        halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and

(b) the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl optionally aresubstituted with one or two substituents independently selected from thegroup consisting of alkyl, halo, and alkylsulfonylamino.

In some embodiments, R² is selected from the group consisting of halo,tert-butyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:

-   -   the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl optionally        are substituted with a substituent selected from the group        consisting of alkyl, halo, and alkylsulfonylamino.

In some embodiments, R² is selected from the group consisting oftert-butyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:

-   -   the C₃-C₆-carbocyclyl and 5-6-membered heterocyclyl optionally        are substituted with a substituent selected from the group        consisting of alkyl, halo, and alkylsulfonylamino.

In some embodiments, R² is selected from the group consisting of halo,alkyl, haloalkyl, carboxyalkyl, hydroxyalkyl, alkyloxyalkyl,trimethylsilylalkynyl, alkylcarbocyclyl, carbocyclyl, alkylheterocyclyl,heterocyclyl, halocarbocyclyl, alkylsulfonylamino, and alkylsulfonyl.

In some embodiments, R² is selected from the group consisting of halo,alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy,alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl,carbocyclyl, and heterocyclyl.

In some embodiments, R² is selected from the group consisting of halo,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl,C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl. In some suchembodiment, R² is selected from the group consisting of halo,C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl,C₆-carbocyclyl, and 5-6-membered heterocyclyl. In other such embodiment,R² is selected from the group consisting of halo, C₁-C₄-alkyl,C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl, phenyl, and5-6-membered heteroaryl.

In some embodiments, R² is selected from the group consisting ofC₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl,C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl. In some suchembodiment, R² is selected from the group consisting of C₁-C₄-alkyl,C₂-C₄-alkenyl, C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl,C₆-carbocyclyl, and 5-6-membered heterocyclyl. In other such embodiment,R² is selected from the group consisting of C₁-C₄-alkyl, C₂-C₄-alkenyl,C₂-C₄-alkynyl, amino, C₁-C₄-alkylsulfonyl, phenyl, and 5-6-memberedheteroaryl.

In some embodiments, R² is selected from the group consisting of halo,C₁-C₄-alkyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl. In somesuch embodiments, R² is selected from the group consisting of halo,C₁-C₄-alkyl, C₆-carbocyclyl, and 5-6-membered heterocyclyl. In othersuch embodiments, R² is selected from the group consisting of halo,C₁-C₄-alkyl, phenyl, and 5-6-membered heteroaryl.

In some embodiments, R² is selected from the group consisting ofC₁-C₄-alkyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl. In somesuch embodiments, R² is selected from the group consisting ofC₁-C₄-alkyl, C₆-carbocyclyl, and 5-6-membered heterocyclyl. In othersuch embodiments, R² is selected from the group consisting ofC₁-C₄-alkyl, phenyl, and 5-6-membered heteroaryl.

In some embodiments, R² is selected from the group consisting of halo,tert-butyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl. In somesuch embodiments, R² is selected from the group consisting of halo,tert-butyl, C₆-carbocyclyl, and 5-6-membered heterocyclyl. In other suchembodiments, R² is selected from the group consisting of halo,tert-butyl, phenyl, and 5-6-membered heteroaryl.

In some embodiments, R² is selected from the group consisting oftert-butyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl. In somesuch embodiments, R² is selected from the group consisting oftert-butyl, C₆-carbocyclyl, and 5-6-membered heterocyclyl. In other suchembodiments, R² is selected from the group consisting of tert-butyl,phenyl, and 5-6-membered heteroaryl.

In some embodiments, R² is selected from the group consisting ofC₃-C₆-carbocyclyl and 5-6-membered heterocyclyl. In some suchembodiments, R² is selected from the group consisting of C₆-carbocyclyl,and 5-6-membered heterocyclyl. In other such embodiments, R² is selectedfrom the group consisting of phenyl and 5-6-membered heteroaryl.

In some embodiments, R² is selected from the group consisting ofC₃-C₆-carbocyclyl and 5-6-membered heterocyclyl. In some suchembodiments, R² is selected from the group consisting of C₆-carbocyclyl,and 5-6-membered heterocyclyl. In other such embodiments, R² is selectedfrom the group consisting of phenyl, furanyl, pyrazolyl, and thiophenyl.

Suitable carbocyclyls for the above embodiments include, for example,cyclopropyl and phenyl.

Suitable heterocyclyls for the above embodiments include, for example,furanyl, pyrazolyl, and thiophenyl.

In some embodiments, R² is selected from the group consisting of halo,alkyl, and alkyloxy.

In some embodiments, R² is alkyl.

In some embodiments, R² is tert-butyl.

B15. Substituent R³

R³ is selected from the group consisting of hydrogen, hydroxy, alkyl,alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy,amino, carbocyclylsulfonyloxy, haloalkylsulfonyloxy, and halo.

In some embodiments, R³ is selected from the group consisting ofhydrogen, hydroxy, alkyloxy, and halo. In some such embodiments, R³ isselected from the group consisting of hydrogen, hydroxy, alkyloxy, andfluoro. In other such embodiments, R³ is selected from the groupconsisting of hydrogen, hydroxy, alkyloxy, and fluoro. In yet other suchembodiments, R³ is selected from the group consisting of hydrogen,hydroxy, alkyloxy, and chloro. In yet other such embodiments, R³ isselected from the group consisting of hydrogen, hydroxy, alkyloxy, andbromo. In further such embodiments, R³ is selected from the groupconsisting of hydrogen, hydroxy, alkyloxy, and iodo.

In some embodiments, R³ is selected from the group consisting ofhydrogen, hydroxy, methoxy, and halo. In some such embodiments, R³ isselected from the group consisting of hydrogen, hydroxy, methoxy, andfluoro. In other such embodiments, R³ is selected from the groupconsisting of hydrogen, hydroxy, methoxy, and chloro. In yet other suchembodiments, R³ is selected from the group consisting of hydrogen,hydroxy, methoxy, and bromo. In further such embodiments, R³ is selectedfrom the group consisting of hydrogen, hydroxy, methoxy, and iodo.

In some embodiments, R³ is selected from the group consisting ofhydrogen, hydroxy, and alkyloxy. In some such embodiments, R³ isselected from the group consisting of hydrogen, hydroxy, methoxy, andethoxy.

In some embodiments, R³ is selected from the group consisting ofhydrogen, amino, alkyl, and alkenyl. In some such embodiments, R³ isselected from the group consisting of hydrogen, methyl, ethyl, ethenyl,and amino.

In some embodiments, R³ is s hydrogen.

In some embodiments, R³ is hydroxy.

In some embodiments, R³ is amino.

In some embodiments, R³ is halo.

In some embodiments, R³ is iodo.

In some embodiments, R³ is alkenyl.

In some embodiments, R³ is ethenyl.

In some embodiments, R³ is alkyl.

In some embodiments, R³ is methyl.

In some embodiments, R³ is ethyl.

In some embodiments, R⁵ is alkyloxy.

In some embodiments, R⁵ is methoxy.

In some embodiments, R⁵ is ethoxy.

B16. Substituent L

L is selected from the group consisting of bond, C(R^(A))═C(R^(B)),C(O)N(R^(C)), N(R^(D))C(O), C₁-C₂-alkylene, CH₂O, OCH₂,cyclopropyl-1,2-ene, CH₂N(R^(L)), N(R^(M))CH₂, C(O)CH₂, and CH₂C(O),wherein R^(A), R^(B), R^(C), R^(D), R^(L), and R^(M) are as discussedbelow.

In some embodiments, L is selected from the group consisting of bond,C(R^(A))═C(R^(B)), C(O)N(R^(C)), N(R^(D))C(O), C₁-C₂-alkylene, CH₂O,OCH₂, cyclopropyl-1,2-ene, CH₂N(R^(L)), and N(R^(M))CH₂.

In some embodiments, L is selected from the group consisting ofC(R^(A))═C(R^(B)), ethylene, and cyclopropyl-1,2-ene.

In some embodiments, L is selected from the group consisting ofC(R^(A))═C(R^(B)), C≡C, C(O)N(R^(C)), N(R^(D))C(O), C₁-C₂-alkylene,CH₂O, OCH₂, cyclopropyl-1,2-ene, CH₂N(R^(L)), N(R^(M))CH₂, C(O)CH₂, andCH₂C(O).

In some embodiments, L is selected from the group consisting ofC(O)N(R^(C)), N(R^(D))C(O), CH₂O, OCH₂, CH₂N(R^(L)), and N(R^(M))CH₂.

In some embodiments, L is a bond. In these embodiments, the compounds offormula (I) correspond in structure to formula I-L0:

In some embodiments, L is C(R^(A))═C(R^(B)), wherein R^(A) and R^(B) areas discussed below. In these embodiments, the compounds of formula (I)correspond in structure to formula I-L1:

In some embodiments, L is CC. In these embodiments, the compounds offormula (I) correspond in structure to formula I-L2:

In some embodiments, L is C(O)N(R^(C)), wherein R^(C) is as discussedbelow. In these embodiments, the compounds of formula (I) correspond instructure to formula I-L3:

In some embodiments, L is N(R^(D))C(O), wherein R^(D) is as discussedbelow. In these embodiments, the compounds of formula (I) correspond instructure to formula I-L4:

In some embodiments, L is C₁-C₂-alkylene. In these embodiments, thecompounds of formula (I) correspond in structure to formula I-L5-1 (if Lis methylene) or I-L5-2 (if L is ethylene):

In some embodiments, L is CH₂O. In these embodiments, the compounds offormula (I) correspond in structure to formula I-L6:

In some embodiments, L is OCH₂. In these embodiments, the compounds offormula (I) correspond in structure to formula I-L7:

In some embodiments, L is cyclopropyl-1,2-ene. In these embodiments, thecompounds of formula (I) correspond in structure to formula I-L8:

In some embodiments, L is C(H)₂N(R^(L)). In these embodiments, thecompounds of formula (I) correspond in structure to formula I-L9:

In some embodiments, L is N(R^(M))C(H)₂. In these embodiments, thecompounds of formula (I) correspond in structure to formula I-L10:

In some embodiments, L is C(O)CH₂. In these embodiments, the compoundsof formula (I) correspond in structure to formula I-L11:

In some embodiments, L is CH₂C(O). In these embodiments, the compoundsof formula (I) correspond in structure to formula I-L12:

B17. Substituents R^(A) and R^(B)

R^(A) and R^(B) are independently selected from the group consisting ofhydrogen, C₁-C₆-alkyl, C₁-C₆-alkyloxy, C₃-C₈-cycloalkyl, and halo,wherein:

the C₁-C₆-alkyl optionally is substituted with one or more substituentsindependently selected from the group consisting of carboxy, halo,hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy,alkyloxy, carbocyclyl, and heterocyclyl.

In some embodiments, one of R^(A) and R^(B) is hydrogen, and the otheris selected from the group consisting of C₁-C₆-alkyl, C₁-C₆-alkyloxy,C₃-C₈-cycloalkyl, and halo, wherein:

the C₁-C₆-alkyl optionally is substituted with one or more substituentsindependently selected from the group consisting of carboxy, halo,hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy,alkyloxy, carbocyclyl, and heterocyclyl.

In some embodiments, R^(A) and R^(B) are independently selected from thegroup consisting of hydrogen, C₁-C₆-alkyl, C₁-C₆-alkyloxy,C₃-C₈-cycloalkyl, and halo.

In some of the above embodiments, R^(A) is hydrogen. In other of theabove embodiments, R^(B) is hydrogen.

In some embodiment, one of R^(A) and R^(B) is hydrogen, and the other isselected from the group consisting of hydrogen, methyl, methoxy, andhalo.

In some embodiments, R^(A) is hydrogen, and R^(B) is selected from thegroup consisting of methyl, methoxy, and halo. In some such embodiments,R^(B) is selected from the group consisting of methyl, methoxy, andfluoro. In other such embodiments, R^(B) is selected from the groupconsisting of methyl, methoxy, and chloro. In yet other suchembodiments, R^(B) is selected from the group consisting of methyl,methoxy, and bromo. In further such embodiments, R^(B) is selected fromthe group consisting of methyl, methoxy, and iodo. In yet further suchembodiments, R^(B) is selected from the group consisting of methyl,methoxy, chloro, and fluoro.

In some embodiments, R^(B) is hydrogen, and R^(A) is selected from thegroup consisting of methyl, methoxy, and halo. In some such embodiments,R^(A) is selected from the group consisting of methyl, methoxy, andfluoro. In other such embodiments, R^(A) is selected from the groupconsisting of methyl, methoxy, and chloro. In yet other suchembodiments, R^(A) is selected from the group consisting of methyl,methoxy, and bromo. In further such embodiments, R^(A) is selected fromthe group consisting of methyl, methoxy, and iodo. In yet further suchembodiments, R^(A) is selected from the group consisting of methyl,methoxy, chloro, and fluoro.

In some embodiments, R^(A) is hydrogen, and R^(B) is hydrogen.

B18. Substituent R^(C)

R^(C) is selected from the group consisting of hydrogen and alkyl. Insome such embodiments, R^(C) is selected from the group consisting ofhydrogen and methyl.

In some embodiments, R^(C) is hydrogen.

In some embodiments, R^(C) is alkyl. In some such embodiments, R^(C) ismethyl.

B19. Substituent R^(D)

R^(D) is selected from the group consisting of hydrogen and alkyl. Insome such embodiments, R^(D) is selected from the group consisting ofhydrogen and methyl.

In some embodiments, R^(D) is hydrogen.

In some embodiments, R^(D) is alkyl. In some such embodiments, R^(D) ismethyl.

B20. Substituent R^(L)

R^(L) is selected from the group consisting of hydrogen, C₁-C₆-alkyl,C₁-C₆-alkyloxy, C₃-C₈-cycloalkyl, and halo, wherein:

the C₁-C₆-alkyl optionally is substituted with one or more substituentsindependently selected from the group consisting of carboxy, halo,hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy,alkyloxy, carbocyclyl, and heterocyclyl.

In some embodiments, R^(L) is selected from the group consisting ofhydrogen, C₁-C₆-alkyl, C₁-C₆-alkyloxy, C₃-C₈-cycloalkyl, and halo.

In some embodiments, R^(L) is selected from the group consisting ofhydrogen, C₁-C₆-alkyl, C₁-C₆-alkyloxy, and halo, wherein:

the C₁-C₆-alkyl optionally is substituted with one or more substituentsindependently selected from the group consisting of carboxy, halo,hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy,alkyloxy, carbocyclyl, and heterocyclyl.

In some embodiments, R^(L) is selected from the group consisting ofhydrogen, C₁-C₆-alkyl, C₁-C₆-alkyloxy, and halo.

In some of the above embodiments, R^(L) is halo. In some suchembodiments, the halo is fluoro. In other such embodiments, the halo ischloro. In yet other such embodiments, the halo is bromo. In furthersuch embodiments, the halo is iodo.

In some of the above embodiments, R^(L) is hydrogen.

In some of the above embodiments, R^(L) is C₁-C₆-alkyl.

In some of the above embodiments, R^(L) is C₁-C₆-alkyloxy.

B21. Substituent R^(M)

R^(M) is selected from the group consisting of hydrogen, C₁-C₆-alkyl,C₁-C₆-alkyloxy, C₃-C₈-cycloalkyl, and halo, wherein:

the C₁-C₆-alkyl optionally is substituted with one or more substituentsindependently selected from the group consisting of carboxy, halo,hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy,alkyloxy, carbocyclyl, and heterocyclyl.

In some embodiments, R^(M) is selected from the group consisting ofhydrogen, C₁-C₆-alkyl, C₁-C₆-alkyloxy, C₃-C₈-cycloalkyl, and halo.

In some embodiments, R^(M) is selected from the group consisting ofhydrogen, C₁-C₆-alkyl, C₁-C₆-alkyloxy, and halo, wherein:

the C₁-C₆-alkyl optionally is substituted with one or more substituentsindependently selected from the group consisting of carboxy, halo,hydroxy, nitro, oxo, amino, cyano, alkyloxycarbonyl, alkylcarbonyloxy,alkyloxy, carbocyclyl, and heterocyclyl.

In some embodiments, R^(M) is selected from the group consisting ofhydrogen, C₁-C₆-alkyl, C₁-C₆-alkyloxy, and halo.

In some of the above embodiments, R^(M) is halo. In some suchembodiments, the halo is fluoro. In other such embodiments, the halo ischloro. In yet other such embodiments, the halo is bromo. In furthersuch embodiments, the halo is iodo.

In some of the above embodiments, R^(M) is hydrogen.

In some of the above embodiments, R^(M) is C₁-C₆-alkyl.

In some of the above embodiments, R^(M) is C₁-C₆-alkyloxy.

B22. Substituent R⁴

R⁴ is selected from the group consisting of C₅-C₆-carbocyclyl,5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ringheterocyclyl, wherein each such substituent optionally is substitutedwith one or more substituents independently selected from the groupconsisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K),wherein R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K) are asdescribed below. In some such embodiments, the C₅-C₆-carbocyclyl,5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ringheterocyclyl are not substituted. In other such embodiments, theC₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl,and fused 2-ring heterocyclyl are substituted with a substituentselected from the group consisting of R^(E), R^(F), R^(G), R^(H), R^(I),R^(J), and R^(K). In other such embodiments, the C₅-C₆-carbocyclyl,5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ringheterocyclyl are substituted with a substituent selected from the groupconsisting of R^(E), R^(F), R^(I), R^(J), and R^(K). In other suchembodiments, the C₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted with asubstituent selected from the group consisting of R^(E), R^(F), andR^(J). In other such embodiments, the C₅-C₆-carbocyclyl, 5-6-memberedheterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclylare substituted with a substituent selected from the group consisting ofR^(F) and R. In other such embodiments, the C₅-C₆-carbocyclyl,5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ringheterocyclyl are substituted with R. In yet other such embodiments, theC₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl,and fused 2-ring heterocyclyl are substituted with two substituentsindependently selected from the group consisting of R^(E), R^(F), R^(G),R^(H), R^(I), R^(J), and R^(K). In yet other such embodiments, theC₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl,and fused 2-ring heterocyclyl are substituted with two substituentsindependently selected from the group consisting of R^(E), R^(F), R^(I),R^(J), and R^(K). In yet other such embodiments, the C₅-C₆-carbocyclyl,5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ringheterocyclyl are substituted with two substituents independentlyselected from the group consisting of R^(E), R^(F), and R^(J). In yetother such embodiments, the C₅-C₆-carbocyclyl, 5-6-memberedheterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclylare substituted with two substituents independently selected from thegroup consisting of R^(E) and R^(J). In further such embodiments, theC₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl,and fused 2-ring heterocyclyl are substituted with three substituentsindependently selected from the group consisting of R^(E), R^(F), R^(G),R^(H), R^(I), R^(J), and R^(K). In further such embodiments, theC₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl,and fused 2-ring heterocyclyl are substituted with three substituentsindependently selected from the group consisting of R^(E), R^(F), R^(I),R^(J), and R^(K). In further such embodiments, the C₅-C₆-carbocyclyl,5-6-membered heterocyclyl, fused 2-ring carbocyclyl, and fused 2-ringheterocyclyl are substituted with three substituents independentlyselected from the group consisting of R^(E), R^(F), and R^(J). Infurther such embodiments, the C₅-C₆-carbocyclyl, 5-6-memberedheterocyclyl, fused 2-ring carbocyclyl, and fused 2-ring heterocyclylare substituted with three substituents independently selected from thegroup consisting of R^(F) and R^(J). In further such embodiments, theC₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl,and fused 2-ring heterocyclyl are substituted with one, two, or threesubstituents independently selected from the group consisting of R^(E),R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In further suchembodiments, the C₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted withone, two, or three substituents independently selected from the groupconsisting of R^(E), R^(F), R^(I), R^(J), and R^(K). In further suchembodiments, the C₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused2-ring carbocyclyl, and fused 2-ring heterocyclyl are substituted withone, two, or three substituents independently selected from the groupconsisting of R^(E), R^(F), and R^(J). In further such embodiments, theC₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring carbocyclyl,and fused 2-ring heterocyclyl are substituted with one, two, or threesubstituents independently selected from the group consisting of R^(F)and R^(J).

In some embodiments, R⁴ is selected from the group consisting ofC₅-C₆-carbocyclyl and 5-6-membered heterocyclyl, wherein each suchsubstituent optionally is substituted with one or more substituentsindependently selected from the group consisting of R^(E), R^(F), R^(G),R^(H), R^(I), R^(J), and R^(K). In some such embodiments, theC₅-C₆-carbocyclyl and 5-6-membered heterocyclyl are not substituted. Inother such embodiments, the C₅-C₆-carbocyclyl and 5-6-memberedheterocyclyl are substituted with a substituent selected from the groupconsisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). Inyet other such embodiments, the C₅-C₆-carbocyclyl and 5-6-memberedheterocyclyl are substituted with two substituents independentlyselected from the group consisting of R^(E), R^(F), R^(G), R^(H), R^(I),R^(J), and R^(K). In further such embodiments, the C₅-C₆-carbocyclyl and5-6-membered heterocyclyl are substituted with three substituentsindependently selected from the group consisting of R^(E), R^(F), R^(G),R^(H), R^(I), R^(J), and R^(K). In further such embodiments, theC₅-C₆-carbocyclyl and 5-6-membered heterocyclyl are substituted withone, two, or three substituents independently selected from the groupconsisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K).

In some embodiments, R⁴ is C₅-C₆-carbocyclyl optionally substituted withone or more substituents independently selected from the groupconsisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). Insome such embodiments, the C₅-C₆-carbocyclyl is not substituted. Inother such embodiments, the C₅-C₆-carbocyclyl is substituted with asubstituent selected from the group consisting of R^(E), R^(F), R^(G),R^(H), R^(I), R^(J), and R^(K). In yet other such embodiments, theC₅-C₆-carbocyclyl is substituted with two substituents independentlyselected from the group consisting of R^(E), R^(F), R^(G), R^(H), R^(I),R^(J), and R^(K). In further such embodiments, the C₅-C₆-carbocyclyl issubstituted with three substituents independently selected from thegroup consisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K).In further such embodiments, the C₅-C₆-carbocyclyl is substituted withone, two, or three substituents independently selected from the groupconsisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K).

In some embodiments, R⁴ is 5-6-membered heterocyclyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), andR^(K). In some such embodiments, the 5-6-membered heterocyclyl is notsubstituted. In other such embodiments, the 5-6-membered heterocyclyl issubstituted with a substituent selected from the group consisting ofR^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In yet other suchembodiments, the 5-6-membered heterocyclyl is substituted with twosubstituents independently selected from the group consisting of R^(E),R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In further suchembodiments, the 5-6-membered heterocyclyl is substituted with threesubstituents independently selected from the group consisting of R^(E),R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In further suchembodiments, the 5-6-membered heterocyclyl is substituted with one, two,or three substituents independently selected from the group consistingof R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K).

In some embodiments, R⁴ is selected from the group consisting of fused2-ring carbocyclyl and fused 2-ring heterocyclyl, wherein each suchsubstituent optionally is substituted with one or more substituentsindependently selected from the group consisting of R^(E), R^(F), R^(G),R^(H), R^(I), R^(J), and R^(K). In some such embodiments, the fused2-ring carbocyclyl and fused 2-ring heterocyclyl are not substituted. Inother such embodiments, the fused 2-ring carbocyclyl and fused 2-ringheterocyclyl are substituted with a substituent selected from the groupconsisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). Inyet other such embodiments, the fused 2-ring carbocyclyl and fused2-ring heterocyclyl are substituted with two substituents independentlyselected from the group consisting of R^(E), R^(F), R^(G), R^(H), R^(I),R^(J), and R^(K). In further such embodiments, the fused 2-ringcarbocyclyl and fused 2-ring heterocyclyl are substituted with threesubstituents independently selected from the group consisting of R^(E),R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In further suchembodiments, the fused 2-ring carbocyclyl and fused 2-ring heterocyclylare substituted with one, two, or three substituents independentlyselected from the group consisting of R^(E), R^(F), R^(G), R^(H), R^(I),R^(J), and R^(K).

In some embodiments, R⁴ is fused 2-ring carbocyclyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), andR^(K). In some such embodiments, the fused 2-ring carbocyclyl is notsubstituted. In other such embodiments, the fused 2-ring carbocyclyl issubstituted with a substituent selected from the group consisting ofR^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In yet other suchembodiments, the fused 2-ring carbocyclyl is substituted with twosubstituents independently selected from the group consisting of R^(E),R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In further suchembodiments, the fused 2-ring carbocyclyl is substituted with threesubstituents independently selected from the group consisting of R^(E),R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In further suchembodiments, the fused 2-ring carbocyclyl is substituted with one, two,or three substituents independently selected from the group consistingof R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K).

In some embodiments, R⁴ is fused 2-ring heterocyclyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), andR^(K). In some such embodiments, the fused 2-ring heterocyclyl is notsubstituted. In other such embodiments, the fused 2-ring heterocyclyl issubstituted with a substituent selected from the group consisting ofR^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In yet other suchembodiments, the fused 2-ring heterocyclyl is substituted with twosubstituents independently selected from the group consisting of R^(E),R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In further suchembodiments, the fused 2-ring heterocyclyl is substituted with threesubstituents independently selected from the group consisting of R^(E),R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K). In further suchembodiments, the fused 2-ring heterocyclyl is substituted with one, two,or three substituents independently selected from the group consistingof R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K).

In some of the above embodiments, the optionally substitutedC₅-C₆-carbocyclyl is selected from the group consisting of cyclopentyl,cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,cyclohexadienyl, and phenyl. In some such embodiments, the optionallysubstituted C₅-C₆-carbocyclyl is phenyl.

In some of the above embodiments, the optionally substitutedC₅-C₆-carbocyclyl is C₅-carbocyclyl. Examples of C₅-carbocyclyls includecyclopentyl, cyclopentenyl, and cyclopentadienyl.

In other of the above embodiments, the optionally substitutedC₅-C₆-carbocyclyl is C₆-carbocyclyl. Examples of C₆-carbocyclyls includecyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl.

In some of the above embodiments, the optionally substituted5-6-membered-heterocyclyl is selected from the group consisting offuranyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl),dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl,pyrrolidinyl, oxazolyl, dihydrooxazolyl, isoxazolyl, dihydroisoxazolyl,oxazolidinyl, isoxazolidinyl, thiazolyl, isothiazolyl, thiazolinyl,isothiazolinyl, thiazolidinyl, isothiazolidinyl, imidazolyl,imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxathiolyl,oxathiolanyl, triazolyl, oxadiazolyl, furazanyl, tetrazolyl,oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiazolidinyl,dihydrooxadiazolyl, dioxazolidinyl, pyranyl, dihydropyranyl,tetrahydropyranyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl,piperidinyl, diazinyl, pyrazinyl, pyridazinyl, pyrimidinyl,dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, triazinyl,dihydrotriazinyl, tetrahydrotriazinyl, triazinanyl, oxazinyl,dihydrooxazinyl, morpholinyl, oxathiazinyl, dihydrooxathiazinyl,oxathiazinanyl, oxadiazinyl, dihydrooxadiazinyl, oxadiazinanyl,thiopyranyl, dihydrothiopyranyl, and tetrahydrothiopyranyl.

In some of the above embodiments, the optionally substituted5-6-membered-heterocyclyl is 5-membered heterocyclyl. Examples of such5-membered heterocyclyl include furanyl, dihydrofuranyl,tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl,tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl,dihydrooxazolyl, isoxazolyl, dihydroisoxazolyl, oxazolidinyl,isoxazolidinyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl,thiazolidinyl, isothiazolidinyl, imidazolyl, imidazolidinyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, oxathiolyl, oxathiolanyl, triazolyl,oxadiazolyl, furazanyl, tetrazolyl, oxatriazolyl, dioxazolyl,oxathiazolyl, oxathiazolidinyl, dihydrooxadiazolyl, and dioxazolidinyl.

In other of the above embodiments, the optionally substituted5-6-membered-heterocyclyl is 6-membered heterocyclyl. Examples of6-membered heterocyclyls include pyranyl, dihydropyranyl,tetrahydropyranyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl,piperidinyl, diazinyl, pyrazinyl, pyridazinyl, pyrimidinyl,dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, triazinyl,dihydrotriazinyl, tetrahydrotriazinyl, triazinanyl, oxazinyl,dihydrooxazinyl, morpholinyl, oxathiazinyl, dihydrooxathiazinyl,oxathiazinanyl, oxadiazinyl, dihydrooxadiazinyl, oxadiazinanyl,thiopyranyl, dihydrothiopyranyl, and tetrahydrothiopyranyl.

In some of the above embodiments, the optionally substituted fused2-ring carbocyclyl is selected from the group consisting ofnaphthalenyl, dihydronaphthalenyl, tetrahydronaphthalenyl,hexahydronaphthalenyl, octahydronaphthalenyl, decahydronaphthalenyl,indenyl, dihydroindenyl, hexahydroindenyl, octahydroindenyl, pentalenyl,octahydropentalenyl, and hexahydropentalenyl. In some such embodiments,the optionally substituted fused 2-ring carbocyclyl is selected from thegroup consisting of naphthalenyl and dihydroindenyl. In some suchembodiments, the optionally substituted fused 2-ring carbocyclyl isnaphthalenyl. In other such embodiments, the optionally substitutedfused 2-ring carbocyclyl is dihydroindenyl. In further such embodiments,the optionally substituted fused 2-ring carbocyclyl is indenyl.

In some of the above embodiments, the optionally substituted fused2-ring heterocyclyl is selected from the group consisting of

X¹, X², and X³ are independently selected from the group consisting of Nand C(H);

X⁴ is selected from the group consisting of N(H), O, and S;

X⁵, X⁶, and X⁷ are independently selected from the group consisting of Nand C(H);

X⁸ is selected from the group consisting of N(H), O, and S;

X⁹ is selected from the group consisting of N(H), O, and S;

X¹⁰, X¹¹, X¹², and X¹³ are independently selected from the groupconsisting of N and C(H);

X¹⁴ is selected from the group consisting of N(H), O, and S;

X¹⁵, X¹⁶, X¹⁷, and X¹⁸ are independently selected from the groupconsisting of N and C(H);

one or more of X¹⁹, X²⁰, and X²¹ is N, and the remaining one(s) is/areC(H);

one or more of X²², X²³, X²⁴, and X²⁵ is N, and the remaining one(s)is/are C(H);

one or more of X²⁶, X²⁷, and X²⁸ is N, and the remaining one(s) is/areC(H);

one or more of X²⁹, X³⁰, X³¹, and X³² is N, and the remaining one(s)is/are C(H);

one or more of X³³, X³⁴, and X³⁵ is N, and the remaining one(s) is/areC(H);

one or more of X³⁶, X³⁷, X³⁸, and X³⁹ is N, and the remaining one(s)is/are C(H);

X⁴⁰, X⁴¹, and X⁴² are independently selected from the group consistingof N and C(H);

one of X⁴³, X⁴⁴, and X⁴⁵ is selected from the group consisting of N(H),O, and S, and the remaining two are C(H)₂;

one of X⁴⁶ and X⁴⁷ is selected from the group consisting of N(H), O, andS, and the other one is C(H)₂;

X⁴⁸, X⁴⁹, X⁵⁰, and X⁵¹ are independently selected from the groupconsisting of N and C(H);

X⁵², X⁵³, and X⁵⁴ are independently selected from the group consistingof N and C(H);

X⁵⁵ is selected from the group consisting of N(H), O, and S;

X⁵⁶, X⁵⁷, and X⁵⁸ are independently selected from the group consistingof N and C(H);

X⁵⁹ is selected from the group consisting of N(H), O, and S;

X⁶⁰ is selected from the group consisting of N(H), O, and S;

X⁶¹, X⁶², X⁶³, and X⁶⁴ are independently selected from the groupconsisting of N and C(H);

X⁶⁵ is selected from the group consisting of N(H), O, and S;

X⁶⁶, X⁶⁷, X⁶⁸, and X⁶⁹ are independently selected from the groupconsisting of N and C(H);

one or more of X⁷⁰, X⁷¹, and X⁷² is N, and the remaining one(s) is/areC(H);

one or more of X⁷³, X⁷⁴, X⁷⁵, and X⁷⁶ is N, and the remaining one(s)is/are C(H); and

one of X⁷⁷ and X⁷⁸ is N(H), and the remaining one is C(H)₂.

In some of the above embodiments, the optionally substituted fused2-ring heterocyclyl is selected from the group consisting of

In some of the above embodiments, the optionally substituted fused2-ring heterocyclyl is selected from the group consisting of:

In some of the above embodiments, X¹, X², and X³ are C(H).

In some of the above embodiments, X⁵, X⁶, and X⁷ are C(H).

In some of the above embodiments, X¹⁰, X¹¹, X¹², and X¹³ are C(H).

In some of the above embodiments, X¹⁵, X¹⁶, X¹⁷, and X¹⁸ are C(H).

In some of the above embodiments, one of X¹⁹, X²⁰, and X²¹ is N.

In some of the above embodiments, one of X²², X²³, X²⁴, and X²⁵ is N.

In some of the above embodiments, one of X²⁶, X²⁷, and X²⁸ is N, and oneof X²⁹, X³⁰, X³¹, and X³² is N.

In some of the above embodiments, X⁴⁰, X⁴¹, and X⁴² are C(H).

In some of the above embodiments, X⁴⁸, X⁴⁹, X⁵⁰, and X⁵¹ are C(H).

In some of the above embodiments, X⁵², X⁵³, and X⁵⁴ are C(H).

In some of the above embodiments, X⁵⁶, X⁵⁷, and X⁵⁸ are C(H).

In some of the above embodiments, X⁵⁶, X⁵⁷, and X⁵⁸ are C(H), and X⁵⁹ isS.

In some of the above embodiments, X⁶¹, X⁶², X⁶³, and X⁶⁴ are C(H).

In some of the above embodiments, X⁶⁶, X⁶⁷, X⁶⁸, and X⁶⁹ are C(H).

In some of the above embodiments, one or more of X⁷⁰, X⁷¹, and X⁷² is N,and the remaining one(s) is/are C(H).

In some of the above embodiments, one or more of X⁷³, X⁷⁴, X⁷⁵, and X⁷⁶is N, and the remaining one(s) is/are C(H).

B23. Substituent R^(E)

Each R^(E) is independently selected from the group consisting of halo,nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido, and aldehydro,wherein the amino optionally is substituted with one or two substituentsindependently selected from the group consisting of alkyl, alkenyl, andalkynyl.

In some embodiment, each R^(E) is independently selected from the groupconsisting of halo, nitro, hydroxy, oxo, carboxy, amino, imino, andaldehydro, wherein the amino optionally is substituted with one or twoindependently selected alkyl.

In some embodiment, each R^(E) is independently selected from the groupconsisting of halo, nitro, hydroxy, oxo, carboxy, amino, imino,aldehydro, and alkylamino.

In some embodiment, each R^(E) is independently selected from the groupconsisting of chloro, fluoro, nitro, hydroxy, oxo, carboxy, amino,imino, aldehydro, and alkylamino.

In some embodiment, each R^(E) is independently selected from the groupconsisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino,and azido. In some such embodiments, each R^(E) is halo. In other suchembodiments, each R^(E) is nitro. In yet other such embodiments, eachR^(E) is hydroxy. In yet other such embodiments, each R^(E) is oxo. Inyet other such embodiments, each R^(E) is carboxy. In yet other suchembodiments, each R^(E) is cyano. In yet other such embodiments, eachR^(E) is amino. In further such embodiments, each R^(E) is imino. In yetfurther such embodiments, each R^(E) is and azido.

In some embodiments, each R^(E) is independently selected from the groupconsisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, andimino.

B24. Substituent R^(F)

Each R^(E) is independently selected from the group consisting of alkyl,alkenyl, and alkynyl, wherein:

-   -   each such substituent optionally is substituted with one or more        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo,        aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl,        alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,        alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy,        alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl,        wherein:        -   the amino, imino, aminosulfonyl, aminocarbonyl, carbocyclyl,            and heterocyclyl optionally are substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl,            alkenylsulfonyl, alkynylsulfonyl, alkylsulfonylamino,            hydroxy, and alkyloxy, wherein:            -   amino portion of the alkylsulfonylamino optionally is                substituted with a substituent selected from the group                consisting of alkyl, alkenyl, and alkynyl.

In some embodiment, each R¹ is independently selected from the groupconsisting of alkyl, alkenyl, and alkynyl, wherein:

-   -   each such substituent optionally is substituted with one or more        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo,        aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl,        alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,        alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy,        alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl,        wherein:        -   the amino, imino, aminosulfonyl, and aminocarbonyl            optionally are substituted with one or two substituents            independently selected from the group consisting of alkyl,            alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl,            alkynylsulfonyl, and alkylsulfonylamino,    -   wherein:        -   amino portion of the alkylsulfonylamino optionally is            substituted with a substituent selected from the group            consisting of alkyl, alkenyl, and alkynyl.

In some of the above embodiments, each R^(F) is independently selectedfrom the group consisting of the alkyl, alkynyl, and alkynyl, whereinsuch substituents are not substituted.

In some embodiments, each R^(F) is independently selected from the groupconsisting of alkyl, alkenyl, and alkynyl, wherein:

-   -   each such substituent optionally is substituted with one or two        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, imino, nitro, oxo, aminosulfonyl,        alkylsulfonyl, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy,        carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:        -   the amino, imino, aminosulfonyl, and aminocarbonyl            optionally are substituted with one or two substituents            independently selected from the group consisting of alkyl,            alkylsulfonyl, and alkylsulfonylamino,    -   wherein:        -   amino portion of the alkylsulfonylamino optionally is            substituted with alkyl.

In some embodiments, each R^(F) is an independently selected alkyloptionally substituted with a substituent selected from the groupconsisting of carboxy, hydroxy, halo, amino, imino, nitro, oxo,aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl, alkylcarbonyloxy,alkyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:

-   -   the amino, imino, aminosulfonyl, and aminocarbonyl optionally        are substituted with one or two substituents independently        selected from the group consisting of alkyl, alkylsulfonyl, and        alkylsulfonylamino, wherein:        -   amino portion of the alkylsulfonylamino optionally is            substituted with alkyl.

In some embodiments, each R^(F) is an independently selected alkyloptionally substituted with a substituent selected from the groupconsisting of carboxy, halo, amino, imino, and aminosulfonyl, wherein:

-   -   the amino, imino, and aminosulfonyl optionally are substituted        with one or two substituents independently selected from the        group consisting of alkyl, alkylsulfonyl, and        alkylsulfonylamino.

In some embodiments, each R^(F) is an independently selected alkyloptionally substituted with amino, wherein the amino optionally issubstituted with alkylsulfonyl.

In some embodiments, each R^(F) is an independently selected alkylsubstituted with amino, wherein the amino is substituted withalkylsulfonyl. In some such embodiments, each R^(F) ismethylsulfonylaminomethyl.

In some embodiments, each R^(F) is independently selected from the groupconsisting of alkyl, alkenyl, and alkynyl, wherein:

-   -   each such substituent optionally is substituted with one, two,        or three substituents independently selected from the group        consisting of carboxy, hydroxy, halo, amino, imino, nitro,        azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl,        alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,        alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy,        alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl.

In some embodiments, each R^(F) is independently selected alkylsubstituted with one or more substituents independently selected fromthe group consisting of carboxy, hydroxy, halo, amino, imino, nitro,azido, oxo, aminosulfonyl, alkylsulfonyl, alkyloxycarbonyl,alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy,alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl.

B25. Substituent R^(G)

Each R^(G) is independently selected from the group consisting ofcarbocyclyl and heterocyclyl, wherein:

-   -   each such substituent optionally is substituted with one or more        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, carboxy, hydroxy, halo, amino, nitro,        azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,        alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy,        alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy,        carbocyclyl, heterocyclyl, cyano, and aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl,            alkynyl, alkylsulfonyl, alkenylsulfonyl, and            alkynylsulfonyl.

In some of the above embodiments, each R^(G) is independently selectedfrom the group consisting of carbocyclyl and heterocyclyl, wherein suchsubstituents are not substituted.

In some embodiments, each R^(G) is independently selected from the groupconsisting of carbocyclyl and heterocyclyl, wherein:

-   -   each such substituent optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl, carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl,        heterocyclyl, cyano, and aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl and            alkylsulfonyl.

In some of the above embodiments, the carbocyclyl is C₃-C₆-carbocyclyl.

In some of the above embodiments, the heterocyclyl is 5-6-memberedheterocyclyl.

B26. Substituent R^(H)

Each R^(H) is independently selected from the group consisting ofalkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, alkenylsulfonyloxy,and alkynylsulfonyloxy, wherein:

-   -   each such substituent optionally is substituted with one or more        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,        alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy,        alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl,        cyano, and aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl,            alkynyl, alkylsulfonyl, alkenylsulfonyl, and            alkynylsulfonyl.

In some of the above embodiments, each R^(H) is independently selectedfrom the group consisting of alkyloxy, alkenyloxy, alkynyloxy,alkylsulfonyloxy, alkenylsulfonyloxy, and alkynylsulfonyloxy, whereinsuch substituents are not substituted.

In some embodiments, each R^(H) is independently selected from the groupconsisting of alkyloxy and alkylsulfonyloxy, wherein:

-   -   each such substituent optionally is substituted with one or two        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl,        heterocyclyl, cyano, and aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl and            alkylsulfonyl.

In some embodiments, each R^(H) is independently selected from the groupconsisting of alkyloxy and alkylsulfonyloxy, wherein:

-   -   each such substituent optionally is substituted with one or two        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano, and        aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl and            alkylsulfonyl.

In some embodiments, each R^(H) is independently selected from the groupconsisting of alkyloxy and alkylsulfonyloxy, wherein:

-   -   each such substituent optionally is substituted with one or two        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano, and        aminocarbonyl.

In some embodiments, each R^(H) is independently selected alkyloxy.

In some embodiments, each R^(H) is independently selectedalkylsulfonyloxy.

B27. Substituent R^(I)

Each R^(I) is independently selected from the group consisting ofalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, aminocarbonyl,alkyloxycarbonyl, carbocyclylcarbonyl, and heterocyclylcarbonyl,wherein:

-   -   (a) the alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl        optionally are substituted with one or more substituents        independently selected from the group consisting of carboxy,        hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,        alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy,        alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl,        cyano, and aminocarbonyl, and    -   (b) the aminocarbonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, alkyloxyalkyl, carbocyclyl,        heterocyclyl, alkylsulfonyl, and alkylsulfonylamino, wherein:        -   the carbocyclyl and heterocyclyl optionally are substituted            with one or two substituents independently selected from the            group consisting of halo, alkyl, and oxo.

In some embodiments, each R^(I) is independently selected from the groupconsisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl, andheterocyclylcarbonyl, wherein such substituents are not substituted.

In some embodiments, each R^(I) is independently selected from the groupconsisting of alkylcarbonyl, aminocarbonyl, alkyloxycarbonyl,carbocyclylcarbonyl, and heterocyclylcarbonyl, wherein:

-   -   (a) the alkylcarbonyl optionally is substituted with a        substituent selected from the group consisting of carboxy,        hydroxy, halo, amino, nitro, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, and aminocarbonyl,        and    -   (b) the aminocarbonyl optionally is substituted with a        substituent selected from the group consisting of alkyl,        alkyloxyalkyl, alkylsulfonyl, and alkylsulfonylamino.

In some embodiments, each R^(I) is independently selected from the groupconsisting of alkylcarbonyl and aminocarbonyl, wherein:

-   -   the aminocarbonyl optionally is substituted with a substituent        selected from the group consisting of alkyl, alkyloxyalkyl,        alkylsulfonyl, and alkylsulfonylamino.

In some embodiment, each R^(I) is independently selected from the groupconsisting of alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, andaminocarbonyl, wherein:

-   -   (a) the alkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl        optionally are substituted with one or more substituents        independently selected from the group consisting of carboxy,        hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,        alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy,        alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl,        cyano, and aminocarbonyl, and    -   (b) the aminocarbonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, and alkylsulfonylamino.

In some of the above embodiments, each R^(I) is independently selectedfrom the group consisting of alkylcarbonyl, alkenylcarbonyl,alkynylcarbonyl, and aminocarbonyl, wherein such substituents are notsubstituted.

In some embodiments, each R^(I) is independently selected from the groupconsisting of alkylcarbonyl and aminocarbonyl, wherein:

-   -   (a) the alkylcarbonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl,        heterocyclyl, cyano, and aminocarbonyl, and    -   (b) the aminocarbonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl and alkylsulfonylamino.

In some embodiments, each R^(I) is independently selected from the groupconsisting of alkylcarbonyl and aminocarbonyl, wherein:

-   -   (a) the alkylcarbonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, cyano, and        aminocarbonyl, and    -   (b) the aminocarbonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl and alkylsulfonylamino.

In some embodiments, each R^(I) is independently selected from the groupconsisting of alkylcarbonyl and aminocarbonyl, wherein:

-   -   the alkylcarbonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl,        heterocyclyl, cyano, and aminocarbonyl.

In some embodiments, each R^(I) is independently selected alkylcarbonyl.

In some embodiments, each R^(I) is independently selected aminocarbonyl.

B28. Substituent R^(J)

Each R^(J) is independently selected from the group consisting ofcarbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino,alkenylcarbonylamino, alkynylcarbonylamino, alkyloxycarbonylamino,alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino,alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino,alkyloxycarbonylaminoimino, alkylsulfonylaminoimino,alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein:

-   -   (a) the amino portion of such substituents optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl,        alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or more substituents independently            selected from the group consisting of alkyl, alkenyl,            alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy,            halo, nitro, cyano, azido, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl,    -   (b) the alkyl, alkenyl, and alkynyl portion of such substituents        optionally is substituted with one or more substituents        independently selected from the group consisting of carboxy,        halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy,        alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy,            and alkynyloxy, wherein:        -   the alkyl optionally is substituted with one or more            hydroxy;    -   (c) the carbocyclyl and heterocyclyl portions of such        substituents optionally are substituted with one or more        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy,        alkynyloxy, halo, nitro, cyano, azido, and amino, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, and alkynyl.

In some embodiment, each R^(J) is independently selected from the groupconsisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino,alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino,alkyloxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino,alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino,aminocarbonylamino, alkylsulfonylaminoimino, alkenylsulfonylaminoimino,and alkynylsulfonylaminoimino, wherein:

-   -   (a) the amino portion of such substituents optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkenyl, alkynyl,        alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or more substituents independently            selected from the group consisting of alkyl, alkenyl,            alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy, alkynyloxy,            halo, nitro, cyano, azido, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl,    -   (b) the alkyl, alkenyl, and alkynyl portion of such substituents        optionally is substituted with one or more substituents        independently selected from the group consisting of carboxy,        halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy,        alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy,            and alkynyloxy, wherein:        -   the alkyl optionally is substituted with one or more            hydroxy;    -   (c) the carbocyclyl and heterocyclyl portions of such        substituents optionally are substituted with one or more        substituents independently selected from the group consisting of        alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy, alkenyloxy,        alkynyloxy, halo, nitro, cyano, azido, and amino, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl, alkenyl, and alkynyl; and

In some of the above embodiments, each R^(J) is independently selectedfrom the group consisting of carbocyclylsulfonylamino,heterocyclylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino,alkynylcarbonylamino, alkyloxycarbonylamino, alkenyloxycarbonylamino,alkynyloxycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino,alkynylsulfonylamino, aminocarbonylamino, alkylsulfonylaminoimino,alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein suchsubstituents are not substituted.

In some embodiments, each R^(J) is independently selected from the groupconsisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino,alkylcarbonylamino, alkyloxycarbonylamino, alkylsulfonylamino,aminocarbonylamino, and alkylsulfonylaminoimino, wherein:

-   -   (a) the amino portion of such substituents optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, carboxy,            hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl,    -   (b) the alkyl portion of such substituents optionally is        substituted with one or two substituents independently selected        from the group consisting of carboxy, halo, oxo, amino,        alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,        carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl and alkyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy;    -   (c) the carbocyclyl and heterocyclyl portions of such        substituents optionally are substituted with one or two        substituents independently selected from the group consisting of        alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, and        amino, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected alkyl.

In some embodiments, each R^(J) is independently selected from the groupconsisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino,alkylsulfonylamino, and alkylsulfonylaminoimino, wherein:

-   -   (a) the amino portion of such substituents optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, carboxy,            hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl,    -   (b) the alkyl portion of such substituents optionally is        substituted with one or two substituents independently selected        from the group consisting of carboxy, halo, oxo, amino,        alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,        carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl and alkyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy;    -   (c) the carbocyclyl and heterocyclyl portions of such        substituents optionally are substituted with one or two        substituents independently selected from the group consisting of        alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, and        amino, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected alkyl.

In some embodiments, each R^(J) is independently selected from the groupconsisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino,alkylsulfonylamino, and alkylsulfonylaminoimino, wherein:

-   -   the amino portion of such substituents optionally is substituted        with a substituent independently selected from the group        consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:    -   (1) the carbocyclyl portion of the carbocyclylalkyl and the        heterocyclyl portion of the heterocyclylalkyl optionally are        substituted with one or two substituents independently selected        from the group consisting of alkyl, carboxy, hydroxy, alkyloxy,        halo, nitro, cyano, oxo, and amino, and    -   (2) the amino portion of the aminocarbonylalkyl optionally is        substituted with one or two substituents independently selected        from the group consisting of alkyl, alkenyl, and alkynyl.

In some embodiments, each R^(J) is independently selected from the groupconsisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino,alkylsulfonylamino, and alkylsulfonylaminoimino, wherein:

-   -   the alkyl portion of the alkylsulfonylamino and        alkylsulfonylaminoimino optionally is substituted with one or        two substituents independently selected from the group        consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl,        alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl,        and cyano, wherein:    -   the amino optionally is substituted with one or two substituents        independently selected from the group consisting of alkyl and        alkyloxy, wherein:    -   the alkyl optionally is substituted with one or more hydroxy.

In some embodiments, each R^(J) is independently selected from the groupconsisting of carbocyclylsulfonylamino, heterocyclylsulfonylamino,alkylsulfonylamino, and alkylsulfonylaminoimino, wherein:

-   -   the carbocyclyl and heterocyclyl portions of such substituents        optionally are substituted with one or two substituents        independently selected from the group consisting of alkyl,        carboxy, hydroxy, alkyloxy, halo, nitro, cyano, and amino.

In some embodiments, each R^(J) is independently selected from the groupconsisting of carbocyclylsulfonylamino and heterocyclylsulfonylamino,wherein:

-   -   the carbocyclyl and heterocyclyl portions of such substituents        optionally are substituted with one or two substituents        independently selected from the group consisting of alkyl,        carboxy, hydroxy, alkyloxy, halo, nitro, cyano, and amino.

In some embodiments, each R^(J) is independently selected from the groupconsisting of alkylsulfonylamino, alkenylsulfonylamino,alkynylsulfonylamino, and alkylsulfonylaminoimino, wherein:

-   -   (a) the amino portion of such substituents optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, carboxy,            hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl,    -   (b) the alkyl, alkenyl, and alkynyl portion of such substituents        optionally is substituted with one or two substituents        independently selected from the group consisting of carboxy,        halo, oxo, amino, alkyloxycarbonyl, alkylcarbonyloxy, hydroxy,        alkyloxy, carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl and alkyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylamino, wherein:

-   -   (a) the amino portion of the alkylsulfonylamino optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, carboxy,            hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl,    -   (b) the alkyl portion of the alkylsulfonylamino optionally is        substituted with one or two substituents independently selected        from the group consisting of carboxy, halo, oxo, amino,        alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,        carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl and alkyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylamino, wherein:

-   -   the amino portion of the alkylsulfonylamino optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, carboxy,            hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylamino, wherein:

-   -   the amino portion of the alkylsulfonylamino optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylamino, wherein:

-   -   the alkyl portion of the alkylsulfonylamino optionally is        substituted with one or two substituents independently selected        from the group consisting of carboxy, halo, oxo, amino,        alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,        carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl and alkyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylamino, wherein:

-   -   the alkyl portion of the alkylsulfonylamino optionally is        substituted with one or two substituents independently selected        from the group consisting of carboxy, halo, oxo, amino,        alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,        carbocyclyl, heterocyclyl, and cyano.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylamino. In some such embodiments, each R^(J) ismethylsulfonylamino.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylaminoimino, wherein:

-   -   (a) the amino portion of the alkylsulfonylaminoimino optionally        is substituted with a substituent independently selected from        the group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, carboxy,            hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl,    -   (b) the alkyl portion of the alkylsulfonylaminoimino optionally        is substituted with one or two substituents independently        selected from the group consisting of carboxy, halo, oxo, amino,        alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,        carbocyclyl, heterocyclyl, and cyano, wherein:    -   the amino optionally is substituted with one or two substituents        independently selected from the group consisting of alkyl and        alkyloxy, wherein:        -   the alkyl optionally is substituted with one or more            hydroxy.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylaminoimino, wherein:

-   -   the amino portion of the alkylsulfonylaminoimino optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl, wherein:        -   (1) the carbocyclyl portion of the carbocyclylalkyl and the            heterocyclyl portion of the heterocyclylalkyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, carboxy,            hydroxy, alkyloxy, halo, nitro, cyano, oxo, and amino, and        -   (2) the amino portion of the aminocarbonylalkyl optionally            is substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylaminoimino, wherein:

-   -   the amino portion of the alkylsulfonylaminoimino optionally is        substituted with a substituent independently selected from the        group consisting of carbocyclylalkyl, heterocyclylalkyl,        alkylcarbonyloxy, aminocarbonylalkyl, alkyl, alkylcarbonyl,        alkyloxycarbonyl, alkyloxyalkyloxycarbonyl,        alkylcarbonyloxyalkyl, and alkylsulfonyl.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylaminoimino, wherein:

-   -   the alkyl portion of the alkylsulfonylaminoimino optionally is        substituted with one or two substituents independently selected        from the group consisting of carboxy, halo, oxo, amino,        alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,        carbocyclyl, heterocyclyl, and cyano, wherein:        -   the amino optionally is substituted with one or two            substituents independently selected from the group            consisting of alkyl and alkyloxy, wherein:            -   the alkyl optionally is substituted with one or more                hydroxy.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylaminoimino, wherein:

-   -   the alkyl portion of the alkylsulfonylaminoimino optionally is        substituted with one or two substituents independently selected        from the group consisting of carboxy, halo, oxo, amino,        alkyloxycarbonyl, alkylcarbonyloxy, hydroxy, alkyloxy,        carbocyclyl, heterocyclyl, and cyano.

In some embodiments, each R^(J) is an independently selectedalkylsulfonylaminoimino. In some such embodiments, each R^(J) ismethylsulfonylaminoimino

In some embodiments, each R^(J) is independently selected from the groupconsisting of alkylcarbonylamino and alkyloxycarbonylamino, wherein:

-   -   the alkyl portion of such substituents optionally is substituted        with one or two substituents independently selected from the        group consisting of carboxy, halo, oxo, amino, alkyloxycarbonyl,        alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl,        and cyano.

B29. Substituent R^(K)

Each R^(K) is independently selected from the group consisting ofaminosulfonyl, alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl,wherein:

-   -   (a) the alkylsulfonyl, alkenylsulfonyl, and alkynylsulfonyl        optionally are substituted with one or more substituents        independently selected from the group consisting of carboxy,        hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,        alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,        alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy,        alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl,        cyano, and aminocarbonyl, wherein:        -   the amino, aminosulfonyl, and aminocarbonyl optionally are            substituted with one or two substituents independently            selected from the group consisting of alkyl, alkenyl, and            alkynyl; and    -   (b) the aminosulfonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        alkyl, alkenyl, and alkynyl.

In some of the above embodiments, each R^(K) is independently selectedfrom the group consisting of amino sulfonyl, alkylsulfonyl,alkenylsulfonyl, and alkynylsulfonyl, wherein such substituents are notsubstituted.

In some embodiments, each R^(K) is independently selected from the groupconsisting of aminosulfonyl and alkylsulfonyl, wherein:

-   -   (a) the alkylsulfonyl optionally is substituted with one or two        substituents independently selected from the group consisting of        carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl,        alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl,        heterocyclyl, cyano, and aminocarbonyl; and    -   (b) the aminosulfonyl optionally is substituted with one or two        substituents independently selected alkyl.

In some embodiments, each R^(K) is independently selected from the groupconsisting of aminosulfonyl and alkylsulfonyl.

C. EMBODIMENTS OF COMPOUNDS OF FORMULA (I)

Various embodiments of substituents R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, L, R^(A), R^(B), R^(C), R^(D), R^(L),R^(M), R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K) have beendiscussed above. These substituent embodiments can be combined to formvarious embodiments of compounds of formula (I). All embodiments ofcompounds of formula (I) formed by combining the substituent embodimentsdiscussed above are within the scope of Applicants' invention, and someillustrative embodiments of the compounds of formula (I) are providedbelow.

In some embodiments, the compounds of formula (I) correspond instructure to formula (I-1), wherein:

is selected from the group consisting of single carbon-carbon bond anddouble carbon-carbon bond;

-   -   R⁵ is selected from the group consisting of hydrogen and methyl;    -   R⁶ is selected from the group consisting of hydrogen, methyl,        and nitrogen-protecting group;    -   R⁷ is hydrogen;    -   R² is selected from the group consisting of alkyl, and        heterocyclyl, wherein:        -   (a) the alkyl optionally is substituted with one or more            halo, and        -   (b) the heterocyclyl optionally is substituted with up to            two alkyl substituents;    -   R³ is selected from the group consisting of alkyl, alkenyl,        alkyloxy, amino, and halo; as to L and R⁴:        -   L is a bond, and R⁴ is selected from the group consisting of            C₅-C₆-carbocyclyl, 5-6-membered heterocyclyl, fused 2-ring            carbocyclyl and fused 2-ring heterocyclyl, wherein each such            substituent optionally is substituted with one or more            substituents independently selected from the group            consisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and            R^(K), or        -   L is C(R^(A))═C(R^(B)), and R⁴ is selected from the group            consisting of C₅-C₆-carbocyclyl and 5-6-membered            heterocyclyl, wherein each such substituent optionally is            substituted with one or more substituents independently            selected from the group consisting of R^(E), R^(F), R^(G),            R^(H), R^(I), R^(J), and R^(K); and        -   R^(A) and R^(B) are independently selected from the group            consisting of hydrogen and C₁-C₆-alkyl.

In some embodiments, the compounds of formula (I) correspond instructure to formula (I-1),

wherein:

-   -   is a double carbon-carbon bond;    -   R⁵ is hydrogen;    -   R⁶ is hydrogen;    -   R⁷ is hydrogen;    -   R² is alkyl;    -   R³ is alkyloxy;    -   L is a bond;    -   R⁴ is fused 2-ring heterocyclyl optionally substituted with        R^(F); and    -   R^(F) is alkyl substituted with amino, wherein the amino is        substituted with alkylsulfonyl.

D. ISOMERS

This invention also is directed, in part, to all isomers of thecompounds of formula (I) (and their salts) (i.e., structural andstereoisomers). Structural isomers include chain and position isomers.Stereoisomers include E/Z isomers (i.e., isomers with regard to one ormore double bonds), enantiomers (i.e., stereo-isomers that have oppositeconfigurations at all stereogenic centers), and diastereoisomers (i.e.,stereo-isomers that have the same configuration at one or morestereogenic centers, but differ at other stereogenic centers).

E. SALTS

This invention also is directed, in part, to all salts of the compoundsof formula (I). A salt of a compound may be advantageous due to one ormore of the salt's properties, such as, for example, enhancedpharmaceutical stability in differing temperatures and humidities, or adesirable solubility in water or other solvents. Where a salt isintended to be administered to a patient (as opposed to, for example,being in use in an in vitro context), the salt preferably ispharmaceutically acceptable and/or physiologically compatible. The term“pharmaceutically acceptable” is used adjectivally in this patentapplication to mean that the modified noun is appropriate for use as apharmaceutical product or as a part of a pharmaceutical product.Pharmaceutically acceptable salts include salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. In general, these salts typically may be prepared by conventionalmeans by reacting, for example, the appropriate acid or base with acompound of the invention.

Pharmaceutically acceptable acid addition salts of the compounds offormula (I) can be prepared from an inorganic or organic acid. Examplesof often suitable inorganic acids include hydrochloric, hydrobromic,hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Suitableorganic acids generally include, for example, aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes oforganic acids. Specific examples of often suitable organic acids includeacetate, trifluoroacetate, formate, propionate, succinate, glycolate,gluconate, digluconate, lactate, malate, tartaric acid, citrate,ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate,glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate,p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate),ethanesulfonate, benzenesulfonate, pantothenate,2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate, algenicacid, beta-hydroxybutyric acid, galactarate, galacturonate, adipate,alginate, bisulfate, butyrate, camphorate, camphorsulfonate,cyclopentanepropionate, dodecylsulfate, glycoheptanoate,glycerophosphate, heptanoate, hexanoate, nicotinate, oxalate, palmoate,pectinate, 2-naphthalesulfonate, 3-phenylpropionate, picrate, pivalate,thiocyanate, tosylate, and undecanoate.

Pharmaceutically acceptable base addition salts of the compounds offormula (I) include, for example, metallic salts and organic salts.Preferred metallic salts include alkali metal (group Ia) salts, alkalineearth metal (group IIa) salts, and other physiologically acceptablemetal salts. Such salts may be made from aluminum, calcium, lithium,magnesium, potassium, sodium, and zinc. Preferred organic salts can bemade from amines, such as tromethamine, diethylamine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine), and procaine. Basicnitrogen-containing groups can be quaternized with agents such as loweralkyl (C₁-C₆) halides (e.g., methyl, ethyl, propyl, and butyl chlorides,bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl,dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl,myristyl, and stearyl chlorides, bromides, and iodides), arylalkylhalides (e.g., benzyl and phenethyl bromides), and others.

F. PURITY

Compounds of formula (I) (and salts thereof) with any level of purity(including pure and substantially pure) are within the scope ofApplicants' invention. The term “substantially pure” in reference to acompound/salt/isomer, means that the preparation/composition containingthe compound/salt/isomer contains more than about 85% by weight of thecompound/salt/isomer, preferably more than about 90% by weight of thecompound/salt/isomer, preferably more than about 95% by weight of thecompound/salt/isomer, preferably more than about 97% by weight of thecompound/salt/isomer, and preferably more than about 99% by weight ofthe compound/salt/isomer.

G. COMPOSITIONS

This invention also is directed, in part, to compositions comprising oneor more compounds and/or salts of the invention (including thecrystalline compounds and salts discussed in section G above). In someembodiments, the compositions comprise one or more substantially phasepure crystalline forms (compounds/salts/solvates/hydrates) discussed insection G above. The compositions can be pharmaceutical compositions.

In some embodiments, the compositions further comprise one or moreadditional therapeutic agents. Such therapeutic agents can, but need notbe, additional HCV inhibitors.

The preferred composition depends on the method of administration, andtypically comprises one or more conventional pharmaceutically acceptablecarriers, adjuvants, and/or vehicles (together referred to as“excipients”). Formulation of drugs is generally discussed in, forexample, Hoover, J., Remington's Pharmaceutical Sciences (MackPublishing Co., 1975) and Ansel's Pharmaceutical Dosage Forms and DrugDelivery Systems (Lippincott Williams & Wilkins, 2005).

Solid dosage forms for oral administration include, for example,capsules, tablets, pills, powders, and granules. In such solid dosageforms, the compounds or salts are ordinarily combined with one or moreexcipients. If administered per os, the compounds or salts can be mixedwith, for example, lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets cancontain a controlled-release formulation, as can be provided in, forexample, a dispersion of the compound or salt in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage formsalso can comprise buffering agents, such as sodium citrate, or magnesiumor calcium carbonate or bicarbonate. Tablets and pills additionally canbe prepared with enteric coatings.

Liquid dosage forms for oral administration include, for example,pharmaceutically acceptable emulsions (including both oil-in-water andwater-in-oil emulsions), solutions (including both aqueous andnon-aqueous solutions), suspensions (including both aqueous andnon-aqueous suspensions), syrups, and elixirs containing inert diluentscommonly used in the art (e.g., water). Such compositions also cancomprise, for example, wetting, emulsifying, suspending, flavoring(e.g., sweetening), and/or perfuming agents.

Parenteral administration includes subcutaneous injections, intravenousinjections, intramuscular injections, intrasternal injections, andinfusion. Injectable preparations (e.g., sterile injectable aqueous oroleaginous suspensions) can be formulated according to the known artusing suitable dispersing, wetting agents, and/or suspending agents.Acceptable vehicles and solvents include, for example, water,1,3-butanediol, Ringer's solution, isotonic sodium chloride solution,bland fixed oils (e.g., synthetic mono- or diglycerides), fatty acids(e.g., oleic acid), dimethyl acetamide, surfactants (e.g., ionic andnon-ionic detergents), and/or polyethylene glycols.

Formulations for parenteral administration may, for example, be preparedfrom sterile powders or granules having one or more of the excipientsmentioned for use in the formulations for oral administration. Acompound or salt of the invention can be dissolved in water,polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseedoil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/orvarious buffers. The pH may be adjusted, if necessary, with a suitableacid, base, or buffer.

Suppositories for rectal administration can be prepared by, for example,mixing a compound or salt of the invention with a suitable nonirritatingexcipient that is solid at ordinary temperatures, but liquid at therectal temperature, and will therefore melt in the rectum to release thedrug. Suitable excipients include, for example, cocoa butter; syntheticmono-, di-, or triglycerides, fatty acids, and/or polyethylene glycols.

Topical administration includes the use of transdermal administration,such as transdermal patches or iontophoresis devices.

Other excipients and modes of administration known in the pharmaceuticalart also may be used.

The preferred total daily dose of the compound or salt (administered insingle or divided doses) is typically from about 0.001 to about 100mg/kg, more preferably from about 0.001 to about 30 mg/kg, and even morepreferably from about 0.01 to about 10 mg/kg (i.e., mg of the compoundor salt per kg body weight). Dosage unit compositions can contain suchamounts or submultiples thereof to make up the daily dose. In manyinstances, the administration of the compound or salt will be repeated aplurality of times. Multiple doses per day typically may be used toincrease the total daily dose, if desired.

Factors affecting the preferred dosage regimen include the type, age,weight, sex, diet, and condition of the patient; the severity of thepathological condition; the severity of the pathological condition; theroute of administration; pharmacological considerations, such as theactivity, efficacy, pharmacokinetic, and toxicology profiles of theparticular compound or salt used; whether a drug delivery system isutilized; and whether the compound or salt is administered as part of adrug combination. Thus, the dosage regimen actually employed can varywidely, and therefore, can derive from the preferred dosage regimen setforth above.

H. KITS

This invention also is directed, in part, to a kit comprising one ormore compounds and/or salts of the in invention. The kit can optionallycontain one or more additional therapeutic agents and/or instructionsfor, for example, using the kit.

I. METHODS OF USE

This invention also is directed, in part, to a method for inhibitingreplication of an RNA virus. The method comprises exposing the virus toone or more compounds and/or salts of this invention. In someembodiments, replication of the RNA virus is inhibited in vitro. Inother embodiments, replication of the RNA virus is inhibited in vivo. Insome embodiments, the RNA virus whose replication is being inhibited isa single-stranded, positive sense RNA virus. In some such embodiments,the RNA virus whose replication is being inhibited is a virus from theFlaviviridae family. In some such embodiments, the RNA virus whosereplication is being inhibited is HCV.

This invention also is directed, in part, to a method for inhibiting HCVRNA polymerase. The method comprises exposing the polymerase with one ormore compounds and/or salts of this invention. In some embodiments, HCVRNA polymerase activity is inhibited in vitro. In other embodiments, HCVRNA polymerase activity is inhibited in vivo.

The term “inhibiting” means reducing the level of RNA virusreplication/HCV polymerase activity either in vitro or in vivo. Forexample, if a compound/salt of the invention reduces the level of RNAvirus replication by at least about 10% compared to the level of RNAvirus replication before the virus was exposed to the compound/salt,then the compound/salt inhibits RNA virus replication. In someembodiments, the compound/salt can inhibit RNA virus replication by atleast about 20%, at least about 30%, at least about 40%, at least about50%, at least about 60%, at least about 70%, at least about 80%, atleast about 90%, or at least about 95%.

This invention also is directed, in part, to a method for treating adisease that can be treated by inhibiting HCV RNA polymerase. Thus, thisinvention also is directed, in part, to a method for treating hepatitisC in an animal in need of such treatment. These methods compriseadministering to the animal one or more compounds and/or salts of theinvention, and, optionally, one or more additional therapeutic agents.In some embodiments, a therapeutically effective amount of thecompound(s) and/or salt(s) is administered to the animal “Treating”means ameliorating, suppressing, eradicating, preventing, reducing therisk of, and/or delaying the onset of the disease being treated.Applicants specifically intend that the term “treating” encompassadministration of the compounds and/or salts of the invention to anHCV-negative patient that is a candidate for an organ transplant. Themethods of treatment are particularly suitable for use with humans, butmay be used with other animals, particularly mammals. A“therapeutically-effective amount” or “effective amount” is an amountthat will achieve the goal of treating the targeted condition.

In some embodiments, the methods comprise combination therapy, whereinthe compound(s) and/or salt(s) of the invention is/are co-administeredwith a second (or even a third, fourth, etc.) compound, such as, forexample, another therapeutic agent used to treat hepatitis C (e.g.,interferon or interferon/ribavirin combination, or an HCV inhibitor suchas, for example, an HCV polymerase inhibitor or an HCV proteaseinhibitor). The compound(s) and/or salt(s) of this invention can also beco-administered with therapeutic agents other than therapeutic agentsused to treat hepatitis C (e.g., anti-HIV agents). In theseco-administration embodiments, the compound(s) and/or salt(s) of theinvention and the second, etc. therapeutic agent(s) may be administeredin a substantially simultaneous manner (e.g., or within about 5 minutesof each other), in a sequential manner, or both. It is contemplated thatsuch combination therapies may include administering one therapeuticagent multiple times between the administrations of the other. The timeperiod between the administration of each agent may range from a fewseconds (or less) to several hours or days, and will depend on, forexample, the properties of each composition and active ingredient (e.g.,potency, solubility, bioavailability, half-life, and kinetic profile),as well as the condition of the patient. The compound(s) and/or salt(s)of this invention and the second, etc. therapeutic agent may also beadministered in a single formulation.

This invention also is directed, in part, to a use of one or morecompounds and/or salts of the invention, and, optionally one or moreadditional therapeutic agents to prepare a medicament. In someembodiments, the medicament is for co-administration with one or moreadditional therapeutic agents.

In some embodiments, the medicament is for inhibiting replication of anRNA virus.

In some embodiments, the medicament is for treating hepatitis C.

This invention also is directed, in part, to one or more compoundsand/or salts of the invention, and, optionally one or more additionaltherapeutic agents, for use as a medicament. In some embodiments, themedicament is for inhibiting replication of an RNA virus. In otherembodiments, the medicament is for treating hepatitis C.

J. METHODS FOR PREPARATION

Additional information about the preparation of compounds of formulas(I) and (II) (and their salts) is provided in the general discussionand/or specific synthesis examples below. In the discussion below, R¹,R², R³, R⁴, R⁵, L, R^(A), R^(B), R^(C), R^(D), R⁶, R^(E), R^(F), R^(G),R^(H), R^(I), R^(J), R^(K), X¹, and X² have the meaning discussed aboveunless otherwise stated.

As described in Scheme 1, compounds of formula (1-4), wherein R² and R³are described in the Summary of the Invention and L-R⁴ is aryl,heteroaryl, styrylaryl or styrylheteroaryl, can be prepared fromcompounds of formula (1-1). Accordingly, compounds of formula (1-1) canbe reacted with a boronic acid of formula (1-2) under Suzuki reactionconditions to supply compounds of formula (1-3). Compounds of formula(1-3) can be converted to compounds of formula (1-4) using a secondSuzuki reaction to introduce L-R⁴ followed by acid hydrolysis to givethe uracil moiety. Compounds of formula (1-4) are representative ofcompounds of formula (I).

As described in Scheme 2, compounds of formula (2-2), wherein R² and R³are described in the Summary of the Invention and L-R⁴ is aryl,heteroaryl, styrylaryl or styrylheteroaryl, and R¹⁰⁰ and R¹⁰¹ areoptionally alkyl groups, can be prepared from compounds of formula(1-3). Compounds of formula (1-3) can be hydrolyzed under acidconditions to reveal a uracil ring. The nitrogens of the uracil can beoptionally alkylated at this point yielding compounds of formula (2-1).Compounds of formula (2-1) can be transformed to compounds of formula(2-2) using a Suzuki reaction to introduce L-R⁴. Compounds of formula(2-2) are representative of compounds of formula (I).

As described in Scheme 3, compounds of formula (3-3), (3-6), and (3-9)wherein R² and R³ are described in the Summary of the Invention and L-R⁴is aryl, heteroaryl, styrylaryl or styrylheteroaryl, can be preparedfrom compounds of formula (1-1). Compounds of formula (1-1) can undergoSuzuki reactions with compounds of formulas (3-1), (3-4), and (3-7) toprovide compounds of formulas (3-2), (3-5), and (3-8), respectively.Compounds of formulas (3-2) and (3-5) can be reacted with R⁴L-B(OH)₂under Suzuki reaction conditions followed by hydrolysis to delivercompounds of formulas (3-3) and (3-6), respectively. Compounds offormula (3-8) can be converted to compounds of formula (3-9), whereinthe L-R⁴ group is introduced under Suzuki reaction conditions. Compoundsof formulas (3-3), (3-6) and (3-9) are representative of compounds offormula (I).

As described in Scheme 4, compounds of formula (4-3) and (4-5), whereinR² and R³ are described in the Summary of the Invention and L-R⁴ isaryl, heteroaryl, styrylaryl or styrylheteroaryl, can be prepared fromcompounds of formula (4-1). Compounds of formula (4-1) can be reactedwith ClCH₂NCO and then treated with base to give compounds of formula(4-2). A Suzuki reaction to introduce L-R⁴ gives compounds of formula(4-3). Compounds of formula (4-1) can also be reacted with EtOC(O)CH₂NCOto give compounds of formula (4-4). Under Suzuki reaction conditions tointroduce L-R⁴, cyclization also occurs giving compounds of formula(4-5). Compounds of formulas (4-3) and (4-5) are representative ofcompounds of formula (I).

As described in Scheme 5, compounds of formula (5-2) and (5-4), whereinR² and R³ are described in the Summary of the Invention and L-R⁴ isaryl, heteroaryl, styrylaryl or styrylheteroaryl, can be prepared fromcompounds of formula (4-1). Compounds of formula (4-1) can be reactedwith Cl(CH₂)₂OC(O)Cl and then treated with a base to give oxazolidinonesof formula (5-1). Introduction of L-R⁴ under Suzuki reaction conditionssupplies compounds of formula (5-2). A similar conversion occurs whencompounds of formula (4-1) are treated with ClCH₂(CH₂)_(p)NCO and then abase to give compounds of formula (5-3). A Suzuki reaction completes thesequence to compounds of formula (5-4).

Also described in Scheme 5 is the preparation of compounds of formula(5-7), wherein R², R³ are described in the Summary of the Invention andL-R⁴ is aryl, heteroaryl, styrylaryl or styrylheteroaryl, from compoundsof formula (5-5). Compounds of formula (5-5) can be reacted withCl(CH₂)₃SO₂Cl and then base to give compounds of formula (5-6). L-R⁴ isintroduced as described for compounds of formulas (5-2) and (5-4) togive compounds of formula (5-7).

Compounds of formulas (5-2), (5-4), and (5-7) are representative ofcompounds of formula (I).

As described in Scheme 6, compounds of formula (6-2) and (6-4), whereinn, m, R², R³, R¹⁵ and R¹⁵ are described in the Summary of the Inventionand L-R⁴ is aryl, heteroaryl, styrylaryl or styrylheteroaryl, can beprepared from compounds of formula (4-1). Compounds of formula (4-1) canbe reacted with carboxylic acids, R¹⁵(CH₂)_(n)CO₂H, under amide bondforming reaction conditions to give compounds of formula (6-1). Suzukireaction conditions deliver L-R⁴ providing compounds of formula (6-2).

Compounds of formula (4-1) can be reacted with isocyanates of formulaR¹⁶(CH₂)_(m)NCO giving compounds of formula (6-3). Compounds are alsoconverted under Suzuki reaction conditions to compounds of formula(6-4).

Compounds of formulas (6-2) and (6-4) are representative of compounds offormula (I).

As described in Scheme 7, compounds of formula (1-4), wherein R² and R³are described in the Summary of the Invention and L-R⁴ is aryl,heteroaryl, styrylaryl or styrylheteroaryl, can be prepared fromcompounds of formula (7-1). Accordingly, compounds of formula (7-1) canbe selectively reacted with a boronic acid of formula (1-2) under Suzukireaction conditions to supply compounds of formula (7-2). Compounds offormula (7-2) can be converted to compounds of formula (1-4) using asecond Suzuki reaction to introduce L-R⁴ followed by acid hydrolysis togive the uracil moiety. Compounds of formula (1-4) are representative ofcompounds of formula (I).

As described in Scheme 8, compounds of formula (8-2) and (8-3), whereinR² and R³ are described in the Summary of the Invention and L-R⁴ isaryl, heteroaryl, styrylaryl or styrylheteroaryl, can be prepared fromcompounds of formula (7-1). Accordingly, compounds of formula (7-1) canbe selectively reacted in a copper mediated coupling reaction withheterocyclic compounds such as but not limited to 2-pyrrolidone orpyridin-2-ol to furnish compounds of formulas (8-1) and (8-3),respectively. Compounds of formulas (8-1) and (8-3) can then be treatedwith R⁴L-B(OH)₂ under Suzuki reaction conditions to provide compounds offormulas (8-2) and (8-4), respectively. Compounds of formulas (8-2) and(8-4) are representative of compounds of formula (I).

As depicted in Scheme 9, compounds of formula (9-4), wherein R² and R³are described in the Summary of the Invention and L-R⁴ is aryl,heteroaryl, styrylaryl or styrylheteroaryl, can be prepared fromcompounds of formula (7-1). Compounds of formula (7-1) can be reactedunder Suzuki reaction conditions with compounds of formula (9-1) tosupply compounds of formula (9-2). Oxidation of compounds of formula(9-2) to give compounds of formula (9-3) can be achieved with a reagentsuch as potassium permanganate. Compounds of formulas (9-3) can then betreated with R⁴L-B(OH)₂ under Suzuki reaction conditions to providecompounds of formulas (9-4). Compounds of formulas (9-4) arerepresentative of compounds of formula (I).

As depicted in Scheme 10, compounds of formula (1-4), wherein R² is arylor heteroaryl, R³ is described in the Summary of the Invention and L-R⁴is aryl, heteroaryl, styrylaryl or styrylheteroaryl, can be preparedfrom compounds of formula (10-1). Compounds of formula (10-1) can bereacted in two sequential Suzuki reaction to deliver compounds offormula (10-2). The nitro group of compounds of formula (10-2) can thenbe reduced to the corresponding aniline by reduction with iron. Theaniline can then be treated with t-butyl nitrite to convert the anilineto the corresponding diazonium salt which in the presence of iodide ionsconverts to the corresponding aryl iodide. Suzuki reaction withcompounds of formula (1-2) followed by treatment with acid givecompounds of formula (1-4). Compounds of formula (1-4) arerepresentative of compounds of formula (I).

As depicted in Scheme 11, compounds of formula (1-4), wherein R² is arylor heteroaryl, R³ is described in the Summary of the Invention and L-R⁴is aryl, heteroaryl, styrylaryl or styrylheteroaryl, can be preparedfrom compounds of formula (10-1) using an alternative sequence. Thenitro group in compounds of formula (10-1) can be converted to thecorresponding pyrrolinyldiazene in a two step procedure. Initialreduction of the nitro group to an aniline can be achieved with iron,and then treatment with sodium nitrite and pyrrolidine under acidconditions deliver the pyrrolinyldiazene. Suzuki reaction conditionsdeliver L-R⁴ group. Then treatment with iodine delivers aryliodides offormula (11-1). Suzuki reaction between compounds of formulas (11-1) and(1-2) gives compounds of formula (11-2). Another Suzuki reactioninstalls R² and after acid conversion to the uracil, compounds offormula (1-4) are obtained. Compounds of formula (1-4) arerepresentative of compounds of formula (I).

As depicted in Scheme 12, compounds of formula (1-4), wherein R² is arylor heteroaryl, R³ is described in the Summary of the Invention and L-R⁴is aryl, heteroaryl, styrylaryl or styrylheteroaryl, can be preparedfrom compounds of formula (10-1). The chemical sequence is essentiallythe same as that described in Scheme 11 except the order of introductionof the R² and L-R⁴ groups is reversed and is useful when it is desirableto introduce the L-R⁴ group later in the synthetic sequence. Thesequence gives compounds of formula (1-4) which are representative ofcompounds of formula (I).

EXAMPLES

The following examples are merely illustrative, and not limiting to thisdisclosure in any way.

Example 1 Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-4-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of 1-bromo-3-tert-butyl-5-iodo-2-methoxybenzene

A solution of 2-bromo-6-tert-butyl-4-iodophenol (5.0 g, 14.08 mmol) inacetone (50 mL) was treated with potassium carbonate (2.92 g, 21.13mmol) and dimethylsulfate (1.95 g, 15.49 mmol) at reflux for 16 hours,cooled and concentrated. The residue was dissolved in ethyl acetate,washed with water, brine, dried (Na₂SO₄), filtered and concentrated invacuo. The crude product was purified on an Isco 40 g silica cartridgeeluting with 2% ethyl acetate in hexane to give the title compound.

Part B. Preparation ofN-(6-(3-bromo-5-tert-butyl-4-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

In a 20 mL microwave tube was mixed the product from Part A (185 mg, 0.5mmol),N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-yl)methanesulfonamide(182 mg, 0.525 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (4.38 mg,0.015 mmol), potassium phosphate (223 mg, 1.050 mmol) andtris(dibenzylideneacetone) dipalladium(0) (4.58 mg, 5.00 mmol) intetrahydrofuran (6.0 mL) and water (2.0 mL). The tube was sealed and themixture was sparged with nitrogen for 5 minutes and then stirred for 4hours. The reaction mixture was partitioned with ethyl acetate and 1 MHCl. The organic layer was washed with saturated NaHCO₃, brine, dried(Na₂SO₄) and filtered. The filtrate was treated with 3-mercaptopropylfunctionalized silica gel (Aldrich catalog #538086), filtered throughdiatomaceous earth and concentrated in vacuo. The crude product waspurified on an Isco 12 g silica cartridge eluting with 4:1 hexane/ethylacetate to give title compound.

Part C. Preparation ofN-(6-(3-tert-butyl-5-(2,4-di-tert-butoxypyrimidin-5-yl)-4-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

In a 5 mL microwave tube was added the product from Part B (0.053 g,0.115 mmol), the product from Example 28 Part B (0.031 g, 0.115 mmol),potassium phosphate (0.049 g, 0.229 mmol) and1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (3.74 mg,5.73 mmol) in a solvent mix of tetrahydrofuran (3.0 mL) and water (1.0mL). The tube was sealed and the mixture was sparged with nitrogen for 5minutes and then stirred at 50° C. for 16 hours. The reaction mixturewas cooled, partitioned with ethyl acetate and 1 M HCl. The organiclayer was washed with saturated NaHCO₃, brine, dried (Na₂SO₄) andfiltered. The filtrate was treated with 3-mercaptopropyl functionalizedsilica gel, filtered through diatomaceous earth and concentrated invacuo. The crude product was purified on an Isco 12 g silica cartridgeeluting with 30% ethyl acetate in hexane to give title compound.

Part D. Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-4-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product from Part C (38 mg, 0.063 mmol) was treated with a mixtureof methanol, concentrated HCl, and water (2.0 mL, 1.0 mL, 1.0 mL) togive a colorless solution followed by rapid formation of a white solid.The mixture was stirred for 1 hour and the solid was collected byfiltration, washed with water and diethyl ether and dried to constantmass to give the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.44(s, 9H) 3.07 (s, 3H) 3.55 (s, 3H) 7.40 (dd, J=8.82, 2.21 Hz, 1H)7.47-7.53 (m, 2H) 7.59 (d, J=2.21 Hz, 1H) 7.69 (d, J=1.84 Hz, 1H) 7.78(dd, J=8.64, 1.65 Hz, 1H) 7.91 (d, J=8.82 Hz, 1H) 7.98 (d, J=8.82 Hz,1H) 8.10 (s, 1H) 9.99 (s, 1H) 11.09 (dd, J=5.88, 1.84 Hz, 1H) 11.31 (d,J=1.84 Hz, 1H).

Example 2 Preparation ofN-((6-(3-tert-butyl-5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxyphenyl)benzo[b]thiophen-3-yl)methyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide

Part A. Preparation of5-(3-bromo-5-tert-butyl-4-methoxyphenyl)-2,4-di-tert-butoxypyrimidine

To a 25 mL round-bottomed flask was added the product from Example 1Part A (36 mg, 1.0 mmol), the product from Example 28 Part B (295 mg,1.1 mmol), potassium phosphate (446 mg, 2.1 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (8.77 mg,0.030 mmol) and tris(dibenzylideneacetone)dipalladium(0) (9.16 mg, 10.0mmol) in tetrahydrofuran (6.0 mL) and water (2.0 mL). The mixture waspurged with nitrogen for 5 minutes and stirred at room temperature for 4hours. The reaction mixture was partitioned with ethyl acetate and 0.1 MHCl. The organic layer was washed with saturated NaHCO₃, brine, dried(Na₂SO₄), filtered and the filtrate was treated with 3-mercaptopropylfunctionalized silica gel, filtered and concentrated in vacuo. The crudeproduct was purified by silica gel flash chromatography eluting withethyl acetate/hexane (0% to 5%) to give the title compound.

Part B. Preparation ofN-((6-(3-tert-butyl-5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxyphenyl)benzo[b]thiophen-3-yl)methyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide

The product from Part A (46.5 mg, 0.10 mmol) andN-(2,4-dimethoxybenzyl)-N-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-3-yl)methyl)methanesulfonamide(51.7 mg, 0.100 mmol) were reacted in the same manner as Example 1 PartC at 50° C. for 2 hours to give crude product which was purified bysilica gel flash chromatography eluting with ethyl acetate/hexane (10%to 25%) to give the title compound.

Part C. Preparation ofN-((6-(3-tert-butyl-5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxyphenyl)benzo[b]thiophen-3-yl)methyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide

To a 25 mL round-bottomed flask was added the product from Part B (58mg, 0.075 mmol) and trifluoroacetic acid (1.0 mL, 12.98 mmol) indichloromethane (4 mL). The mixture was stirred at room temperature for1 hour. The solvent was concentrated in vacuo and the product wastriturated with 1% methanol/dichloromethane to give the title compound.¹H NMR (300 MHz, DMSO-d₆) ppm 1.42 (s, 9H) 2.95 (s, 3H) 3.19 (s, 3H)4.44 (d, J=6.25 Hz, 2H) 7.38 (d, J=2.21 Hz, 1H) 7.47 (d, J=2.21 Hz, 1H)7.62 (m, 2H) 7.70 (m, 2H) 8.00 (d, J=8.46 Hz, 1H) 8.13 (d, J=1.02 Hz,1H) 11.12 (dd, J=5.88, 1.84 Hz, 1H) 11.22 (d, J=1.84 Hz, 1H).

Example 3 Preparation ofN-((6-(3-tert-butyl-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxyphenyl)-1H-inden-3-yl)methyl)methanesulfonamide

Part A. Preparation ofN-((6-(3-tert-butyl-5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxyphenyl)-1H-inden-3-yl)methyl)methanesulfonamide

The product from Example 2 Part A (55.9 mg, 0.12 mmol) andN-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-inden-3-yl)methyl)methanesulfonamide(41.9 mg, 0.120 mmol) were reacted in the same manner as Example 2 PartB. The crude product was purified by silica gel flash chromatographyeluting with ethyl acetate/hexane (5% to 25%) to give the titlecompound.

Part B. Preparation ofN-((6-(3-tert-butyl-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxyphenyl)-1H-inden-3-yl)methyl)methanesulfonamide

To a 25 mL round-bottomed flask was added the product from Part A (33mg, 0.054 mmol) in the mixed solvent of methanol (2 mL) and 5 M HCl (2mL). The mixture was stirred at room temperature for 1 hour, filtered,washed with water, diethyl ether and dried to give the title compound.¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.41 (s, 9H) 2.96 (s, 3H) 3.20 (s, 3H)3.46 (s, 2H) 4.18 (d, J=5.15 Hz, 2H) 6.54 (s, 1H) 7.32 (d, J=2.21 Hz,1H) 7.41 (d, J=2.21 Hz, 1H) 7.49 (m, 2H) 7.57 (d, J=7.71 Hz, 1H) 7.64(s, 1H) 7.66 (s, 1H) 11.09 (s, 1H) 11.19 (s, 1H).

Example 4 Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxystyryl)phenyl)methanesulfonamide

Part A. Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxystyryl)phenyl)methanesulfonamide

The product from Example 2 Part A (55.9 mg, 0.12 mmol) and(E)-4-(methylsulfonamido) styrylboronic acid (28.9 mg, 0.120 mmol) werereacted in the same manner as Example 2 Step B. The crude product waspurified by silica gel flash chromatography eluting with ethylacetate/hexane (5% to 25%) to give the title compound.

Part B. Preparation of(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxystyryl)phenyl)methanesulfonamide

The product from Part A (39 mg, 0.067 mmol) was reacted in the samemanner as Example 3 Step B to give the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.38 (s, 9H) 3.01 (s, 3H) 3.74 (s, 3H) 7.21 (m, 4H) 7.38(d, J=2.21 Hz, 1H) 7.62 (d, J=8.46 Hz, 2H) 7.66 (m, 2H) 9.83 (s, 1H)11.12 (s, 1H) 11.22 (s, 1H).

Example 5 Preparation of5-(3-bromo-5-tert-butyl-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione

The product from Example 2 Part A (56 mg, 0.120 mmol) was reacted in thesame manner as Example 2 Part C and the crude product was trituratedwith 1% methanol/dichloromethane to give the title compound. ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.36 (s, 9H) 3.85 (s, 3H) 7.44 (d, J=2.21 Hz, 1H)7.68 (d, J=2.21 Hz, 1H) 7.70 (s, 1H) 11.19 (s, 1H) 11.25 (s, 1H).

Example 6N-((6-(3-tert-butyl-2-methoxy-5-(1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl)-1H-inden-3-yl)methyl)methanesulfonamide

Part A. Preparation of 1:5-(3-bromo-5-tert-butyl-4-methoxyphenyl)-1-methylpyrimidine-2,4(1H,3H)-dioneand 2:5-(3-bromo-5-tert-butyl-4-methoxyphenyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione

The product from Example 5 (750 mg, 2.123 mmol) and sodium hydroxide(2.336 mL, 2.336 mmol) were combined in N,N-dimethylformamide (10 mL).Dimethyl sulfate (0.223 mL, 2.336 mmol) was added and stirred for 2hours. The reaction mixture was partitioned with ethyl acetate and H₂O.The organic layer was washed with brine, dried (Na₂SO₄), filtered andconcentrated in vacuo to give crude product which was purified by silicagel flash chromatography eluting with methanol/dichloromethane (1% to5%) to give the title compound 1 and title compound 2.

Part B.N-((6-(3-tert-butyl-2-methoxy-5-(1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl)-1H-inden-3-yl)methyl)methanesulfonamide

The product from Part A(compound 1) (55.1 mg, 0.15 mmol) andN-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-inden-3-yl)methyl)methanesulfonamide(52.4 mg, 0.150 mmol) were reacted in the same manner as Example 2 PartB to give crude product which was purified by silica gel flashchromatography eluting with ethyl acetate/hexane (20% to 60%) to givethe title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.41 (s, 9H) 2.96(s, 3H) 3.21 (s, 3H) 3.31 (s, 3H) 3.47 (s, 2H) 4.18 (d, J=4.78 Hz, 2H)6.55 (s, 1H) 7.35 (d, J=2.21 Hz, 1H) 7.46 (d, J=2.21 Hz, 1H) 7.50 (m,2H) 7.58 (d, J=8.01 Hz, 1H) 7.64 (s, 1H) 7.94 (s, 1H) 11.41 (s, 1H).

Example 7N-(6-(3-tert-butyl-2-methoxy-5-(1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Example 6 Part A (compound 1) (55.1 mg, 0.15 mmol) andN-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-yl)methanesulfonamide(52.1 mg, 0.150 mmol) were reacted in the same manner as Example 2 PartB to give crude product which was triturated withmethanol/dichloromethane to give the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.43 (s, 9H) 3.08 (s, 3H) 3.21 (s, 3H) 3.32 (s, 3H) 7.41(dd, J=8.82, 2.21 Hz, 1H) 7.45 (d, J=2.21 Hz, 1H) 7.51 (d, J=2.57 Hz,1H) 7.68 (dd, J=8.46, 1.47 Hz, 1H) 7.72 (d, J=1.84 Hz, 1H) 7.93 (d,J=8.46 Hz, 1H) 7.98 (m, 3H) 10.02 (s, 1H) 11.42 (s, 1H).

Example 8N-(6-(3-tert-butyl-5-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product from Example 6 Part A (compound 2) (57.2 mg, 0.15 mmol) andN-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-yl)methanesulfonamide(52.1 mg, 0.150 mmol) were reacted in the same manner as Example 2 PartB to give crude product which was triturated withmethanol/dichloromethane to give the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.43 (s, 9H) 3.08 (s, 3H) 3.22 (s, 3H) 3.25 (s, 3H) 3.39(s, 3H) 7.41 (dd, J=8.82, 2.21 Hz, 1H) 7.45 (d, J=2.21 Hz, 1H) 7.53 (d,J=2.57 Hz, 1H) 7.69 (dd, J=8.46, 1.47 Hz, 1H) 7.72 (d, J=1.84 Hz, 1H)7.93 (d, J=8.46 Hz, 1H) 7.97 (d, J=8.82 Hz, 1H) 8.00 (s, 1H) 8.03 (s,1H) 10.02 (s, 1H).

Example 9 Preparation ofN-(6-(3-tert-butyl-2-methoxy-5-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of 3-bromo-2-tert-butoxypyridine

To a solution of 3-bromo-2-fluoropyridine (500 mg, 2.84 mmol) inanhydrous tetrahydrofuran (10 mL) under nitrogen was added potassiumtert-butoxide (540 mg, 4.8 mmol) in portions over 30 minutes at 25° C.,and stirring was continued for 4 hours at 25° C. The mixture wasconcentrated in vacuo and purified by silica gel flash chromatographyeluting with dichloromethane/hexanes (50% to 100%) to give the titlecompound.

Part B. Preparation of 2-tert-butoxypyridin-3-ylboronic acid

To a solution of the product from Part A (540 mg, 2.347 mmol) inanhydrous tetrahydrofuran (10 mL) under nitrogen at −78° C. was added1.6 M butyllithium in hexanes (1.760 mL, 2.82 mmol) dropwise. Thesolution was stirred for 10 minutes and treated dropwise with a solutionof tributyl borate (0.886 mL, 3.29 mmol) in anhydrous tetrahydrofuran (2mL), stirred at −78° C. for 3 hours, then allowed to warm to 0° C.,cooling the reaction in an ice bath. The reaction mixture was treatedwith cold 1 M HCl (2.35 mL), followed by ice cold H₂O (5 mL), then thelayers were separated and the aqueous phase extracted with diethylether. The organic extracts were extracted with cold 2 M aqueous NaOHand the combined alkaline phases were neutralized to pH˜6 with 6 Maqueous HCl while stirring and cooling in an ice bath, causing theproduct to precipitate. The solid was collected by filtration and driedto give the title compound.

Part C. Preparation of3-(3-bromo-5-tert-butyl-4-methoxyphenyl)-2-tert-butoxypyridine

The product from Example 1 Part A (151 mg, 0.410 mmol) and the productfrom Part B (80 mg, 0.41 mmol) were reacted in the same manner asExample 1 Part B for 48 hours to give crude product which was purifiedon an Isco 12 g silica cartridge eluting with 5% ethyl acetate in hexaneto give the title compound.

Part D. Preparation ofN-(6-(5-(2-tert-butoxypyridin-3-yl)-3-tert-butyl-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product from Part C (130 mg, 0.331 mmol) andN-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-yl)methanesulfonamide(115 mg, 0.331 mmol) were reacted in the same manner as Example 1 Part Cto give crude product which was purified on an Isco 12 g silicacartridge eluting with 10% ethyl acetate in hexane to give the titlecompound.

Part E. Preparation ofN-(6-(3-tert-butyl-2-methoxy-5-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part D (65 mg, 0.122 mmol) was reacted in the samemanner as Example 1 Part D to give the title compound. mp>300° C.; ¹HNMR (300 MHz, DMSO-d₆) δ ppm 1.44 (s, 9H) 3.08 (s, 3H) 3.22 (s, 3H) 6.29(t, J=6.62 Hz, 1H) 7.34-7.38 (m, 1H) 7.41 (dd, J=8.82, 2.21 Hz, 1H)7.62-7.76 (m, 5H) 7.93 (d, J=8.46 Hz, 1H) 7.97 (d, J=8.82 Hz, 1H) 8.02(s, 1H) 10.01 (s, 1H) 11.74 (s, 1H).

Example 10 Preparation ofN-(6-(3-tert-butyl-2-methoxy-5-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The title compound was prepared according to the procedure from Example9 substituting 5-bromo-2-fluoropyridine (1.0 g, 5.57 mmol) for3-bromo-2-fluoropyridine in Part A to give the title compound. mp>300°C.; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.45 (s, 9H) 3.08 (s, 3H) 3.20 (s,3H) 6.43 (d, J=9.56 Hz, 1H) 7.32-7.46 (m, 3H) 7.70-7.76 (m, 3H) 7.87(dd, J=9.56, 2.94 Hz, 1H) 7.92 (d, J=8.82 Hz, 1H) 7.97 (d, J=8.82 Hz,1H) 8.08 (s, 1H) 10.02 (s, 1H) 11.85 (s, 1H).

Example 11 Preparation ofN-(6-(5-tert-butyl-2′,4′-difluoro-4-methoxybiphenyl-3-yl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of3′-bromo-5′-tert-butyl-2,4-difluoro-4′-methoxybiphenyl

The product from Example 1 Part A (0.185 g, 0.501 mmol) and2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5-difluorobenzene(0.120 g, 0.501 mmol) were reacted in the same manner as Example 1 PartB for 16 hours. The crude product was purified on an Isco 12 g silicacartridge eluting with 5% ethyl acetate in hexane to give the titlecompound.

Part B. Preparation ofN-(6-(5-tert-butyl-2′,4′-difluoro-4-methoxybiphenyl-3-yl)naphthalen-2-yl)methanesulfonamide

The product from Part A (140 mg, 0.394 mmol) was reacted in the samemanner as Example 1 Part C for 16 hours. The crude product was purifiedon an Isco 40 g silica cartridge eluting with 40% ethyl acetate inhexane to give the title compound. mp 225-228. ° C.; ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.45 (s, 9H) 3.08 (s, 3H) 3.25 (s, 3H) 7.14-7.23 (m, 1H)7.32 (d, J=2.57 Hz, 1H) 7.35-7.45 (m, 3H) 7.61-7.77 (m, 3H) 7.90-8.00(m, 2H) 8.06 (s, 1H) 10.03 (s, 1H).

Example 12 Preparation of5-(3-tert-butyl-4-methoxy-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)phenyl)pyrimidine-2,4(1H,3H)-dione

Part A. Preparation of5-(3-tert-butyl-5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-one

A solution of Example 2 Part A (0.150 g, 0.32 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one(0.092 g, 0.36 mmol) were reacted in the same manner as Example 50 PartA using 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex as catalyst at 100° C. for 1.5 hours in themicrowave and for 4 hours at 100° C. in an oil bath to give crudeproduct which was purified by silica gel flash chromatography elutingwith ethyl acetate/hexane (0% to 15%) to give the title compound.

Part B. Preparation of5-(3-tert-butyl-4-methoxy-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)phenyl)pyrimidine-2,4(1H,3H)-dione

A solution of the product from Part A (0.028 g, 0.054 mmol) was reactedin the same manner as Example 1 Part D at room temperature to give thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.41 (s, 9H) 2.65-2.74(m, 2H) 3.12-3.21 (m, 2H) 3.24 (s, 3H) 7.37 (d, J=2.21 Hz, 1H) 7.50 (d,J=2.21 Hz, 1H) 7.57-7.62 (m, 1H) 7.72 (d, J=8.46 Hz, 3H) 11.13 (s, 1H)11.23 (s, 1H).

Example 13 Preparation of5-(3-tert-butyl-5-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione

Part A. Preparation of5-(5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxy-3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-ol

A solution of the product from Example 12 Part A (0.082 g, 0.16 mmol) inmethanol (1.5 mL) and tetrahydrofuran (1.5 mL) at room temperature wastreated with sodium borohydride (0.012 g, 0.32 mmol) and stirred for 1hour. The solution was poured into 0.1 M HCl, extracted into ethylacetate, dried over sodium sulfate and concentrated in vacuo to give thetitle compound.

Part B. Preparation of5-(3-tert-butyl-5-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione

A solution of the product from Part A (0.025 g, 0.05 mmol) was reactedin the same manner as Example 1 Part D at room temperature to give thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.40 (s, 9H) 2.00 (ddd,J=12.96, 8.73, 4.04 Hz, 1H) 2.27-2.41 (m, J=13.14, 8.00, 6.62, 6.43 Hz,1H) 2.77-2.90 (m, 1H) 2.96-3.10 (m, 1H) 3.21 (s, 3H) 4.82 (dd, J=6.25,4.04 Hz, 1H) 7.29 (d, J=2.21 Hz, 1H) 7.35-7.49 (m, 4H) 7.66 (s, 1H)11.10 (s, 1H) 11.19 (s, 1H).

Example 14 Preparation ofN-(6-(3-tert-butyl-2-methoxy-5-ureidophenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)urea

To a solution of 3-tert-butyl-5-iodo-4-methoxyaniline (915 mg, 3.0 mmol)in dioxane (20 mL) at 0° C. was added chloroacetyl isocyanate (0.256 mL,3.00 mmol) dropwise to give a solution that was stirred at roomtemperature for 3 hours. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.904 mL,6.00 mmol) was added and the solution was stirred for 18 hours andpartitioned between ethyl acetate and 1 M HCl. The ethyl acetate waswashed with H₂O, brine and dried (Na₂SO₄), filtered and concentrated invacuo. The crude product was purified on an Isco 40 g silica cartridgeeluting with methanol/dichloromethane (0% to 5%) to give the titlecompound.

Part B. Preparation ofN-(6-(3-tert-butyl-2-methoxy-5-ureidophenyl)naphthalen-2-yl)methanesulfonamide

The product from Part A (52 mg, 0.149 mmol) was reacted in the samemanner as Example 1 Part B at 50° C. for 18 hours to give material thatwas dissolved in hot tetrahydrofuran (10 mL), treated withmercaptopropyl functionalized silica for 30 minutes and filtered througha diatomaceous earth plug. The filtrate was concentrated in vacuo togive the title compound. mp>300° C.; ¹H NMR (300 MHz, DMSO-d₆) δ ppm1.39 (s, 9H) 3.07 (s, 3H) 3.14 (s, 3H) 5.76 (s, 2H) 7.18 (d, J=2.57 Hz,1H) 7.40 (dd, J=8.64, 2.02 Hz, 1H) 7.47 (d, J=2.57 Hz, 1H) 7.64 (dd,J=8.46, 1.84 Hz, 1H) 7.71 (d, J=2.21 Hz, 1H) 7.91 (d, J=8.82 Hz, 1H)7.94 (s, 1H) 7.97 (d, J=8.82 Hz, 1H) 8.49 (s, 1H) 10.00 (s, 1H).

Example 15 Preparation ofN-(6-(3-tert-butyl-5-(2-hydroxy-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of ethyl2-(3-(3-tert-butyl-5-iodo-4-methoxyphenyl)ureido)acetate

To a solution of 3-tert-butyl-5-iodo-4-methoxyaniline (458 mg, 1.5 mmol)in dioxane (5 mL) was added ethyl isocyanatoacetate (0.168 mL, 1.500mmol) dropwise producing a solution that was stirred at room temperaturefor 16 hours. The reaction mixture was concentrated and the product wastriturated in 9:1 hexane/ethyl acetate. The resulting solid wascollected by filtration and dried to give the title compound.

Part B. Preparation ofN-(6-(3-tert-butyl-5-(2-hydroxy-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product from Part A (87 mg, 0.2 mmol) was reacted in the same manneras Example 1 Part B at 50° C. for 18 hours. The crude product waspurified on an Isco 12 g silica cartridge eluting withmethanol/dichloromethane (0.5% to 3%). The collected material wastriturated in 1:1:1 methanol/ethyl acetate/hexane and filtered tocollect the title compound m.p. 293-295° C.; ¹H NMR (300 MHz, DMSO-d₆) δppm 1.42 (s, 9H) 3.08 (s, 3H) 3.25 (s, 3H) 4.05 (s, 2H) 7.27 (s, 2H)7.42 (dd, J=8.82, 2.21 Hz, 1H) 7.67 (dd, J=8.46, 1.84 Hz, 1H) 7.73 (d,J=1.84 Hz, 1H) 7.89-8.03 (m, 3H) 8.29 (s, 1H) 10.03 (s, 1H).

Example 16 Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxoimidazolidin-1-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)imidazolidine-2,4-dione

3-tert-Butyl-5-iodo-4-methoxyaniline (915 mg, 3.0 mmol) and chloroacetylisocyanate (0.256 mL, 3.00 mmol) were reacted in the same manner asExample 14 Part A to give crude product which was purified on an Isco 40g silica cartridge eluting with methanol/dichloromethane (0% to 5%) togive the title compound.

Part B. Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxoimidazolidin-1-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product from Part A (78 mg, 0.20 mmol) was reacted in the samemanner as Example 1 Part B at 50° C. for 18 hours. The crude product waspurified on an Isco 12 g silica cartridge eluting withmethanol/dichloromethane (0.5% to 3%) and the resulting material wasthen triturated in 3:1 ethyl acetate/hexane and filtered to give thetitle compound. m.p. 280° C.; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.41 (s,9H) 3.08 (s, 3H) 3.17 (s, 3H) 4.52 (s, 2H) 7.38-7.45 (m, 2H) 7.62 (d,J=2.57 Hz, 1H) 7.64-7.74 (m, 2H) 7.90-8.04 (m, 3H) 10.05 (s, 1H) 11.14(s, 1H).

Example 17 Preparation ofN-(6-(3-tert-butyl-2-methoxy-5-(3-phenylureido)phenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)-3-phenylurea

3-tert-Butyl-5-iodo-4-methoxyaniline (305 mg, 1 mmol) and phenylisocyanate (0.109 mL, 1.000 mmol) were reacted in the same manner asExample 15 Part A to give the title compound.

Part B. Preparation ofN-(6-(3-tert-butyl-2-methoxy-5-(3-phenylureido)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part A (85 mg, 0.20 mmol) was reacted in the samemanner as Example 1 Part B at 50° C. for 18 hours. The reaction mixturewas cooled and the solid was collected by filtration, washed repeatedlywith water and the crude product was triturated in 4 mL methanol, thesolid collected and dried to give the title compound. m.p.>300; ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.41 (s, 9H) 3.08 (s, 3H) 3.16 (s, 3H) 6.95 (t,J=7.35 Hz, 1H) 7.21-7.31 (m, 3H) 7.38-7.47 (m, 3H) 7.50 (d, J=2.94 Hz,1H) 7.67 (dd, J=8.46, 1.84 Hz, 1H) 7.73 (d, J=1.84 Hz, 1H) 7.92 (d,J=8.82 Hz, 1H) 7.96-8.02 (m, 2H) 8.59 (s, 1H) 8.64 (s, 1H) 10.02 (s,1H).

Example 18 Preparation ofN-(6-(3-tert-butyl-5-(3-isopropylureido)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)-3-isopropylurea

3-tert-Butyl-5-iodo-4-methoxyaniline (305 mg, 1 mmol) and isopropylisocyanate were reacted in the same manner as Example 15 Part A to givethe title compound

Part B. Preparation ofN-(6-(3-tert-butyl-5-(3-isopropylureido)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product from Part A (78 mg, 0.20 mmol) was reacted in the samemanner as Example 1 Part B at 50° C. for 18 hours. The crude product wastriturated in 4 mL 1:1 ethyl acetate/methanol and the solid wascollected and dried to give the title compound. m.p.>300; ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.08 (d, J=6.62 Hz, 6H) 1.39 (s, 9H) 3.07 (s, 3H)3.14 (s, 3H) 3.64-3.82 (m, 1H) 5.88 (d, J=7.72 Hz, 1H) 7.20 (d, J=2.57Hz, 1H) 7.39 (d, J=2.21 Hz, 1H) 7.42 (d, J=2.57 Hz, 1H) 7.64 (dd,J=8.46, 1.84 Hz, 1H) 7.71 (d, J=2.21 Hz, 1H) 7.90 (d, J=8.82 Hz, 1H)7.94 (s, 1H) 7.97 (d, J=9.19 Hz, 1H) 8.26 (s, 1H) 10.01 (s, 1H).

Example 19 Preparation of tert-butyl2-(3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido)naphthalen-2-yl)phenylamino)-2-oxoethylcarbamate

Part A. Preparation of tert-butyl2-(3-tert-butyl-5-iodo-4-methoxyphenylamino)-2-oxo ethylcarbamate

3-tert-Butyl-5-iodo-4-methoxyaniline (0.153 g, 0.5 mmol),N-(tert-butoxycarbonyl)glycine (0.096 g, 0.55 mmol),N,N-diisopropylethylamine (0.173 mL, 1.000 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.177 g, 0.550 mmol) were combined in dimethyl sulfoxide (2.5 mL),stirred for 48 hours and partitioned between ethyl acetate and water.The organic layer was washed with brine, dried (Na₂SO₄) and concentratedin vacuo. The crude product was purified on an Isco 12 g silicacartridge eluting with ethyl acetate/hexane (0% to 25%) to give thetitle compound.

Part B. Preparation of tert-butyl2-(3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido)naphthalen-2-yl)phenylamino)-2-oxoethylcarbamate

The product from Part A (230 mg, 0.50 mmol) was reacted in the samemanner as Example 1 Part B at 50° C. for 18 hours. The crude product wastriturated in 15 mL of 1:1:1 dichloromethane/methanol/ethyl acetate andfiltered to remove a small amount of solid. The filtrate was thenconcentrated and this residue was triturated with 5 mL of 4:1dichloromethane/methanol mixture and filtered to collect the titlecompound. mp 221-223° C.; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.39 (s, 9H)1.40 (s, 9H) 3.08 (s, 3H) 3.16 (s, 3H) 3.70 (d, J=5.88 Hz, 2H) 7.03 (t,J=6.07 Hz, 1H) 7.41 (dd, J=8.82, 1.84 Hz, 1H) 7.46 (d, J=2.57 Hz, 1H)7.60-7.68 (m, 2H) 7.72 (d, J=1.84 Hz, 1H) 7.91 (s, 1H) 7.93-8.02 (m, 2H)9.88 (s, 1H) 10.02 (s, 1H).

Example 20 Preparation of2-amino-N-(3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido)naphthalen-2-yl)phenyl)acetamide

The product from Example 19 Part B (70 mg, 0.126 mmol) was reacted inthe same manner as Example 2 Part C to give the title compound as thetrifluoroacetic acid salt. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.41 (s, 9H)3.09 (s, 3H) 3.18 (s, 3H) 3.69-3.83 (m, 2H) 7.42 (dd, J=8.82, 2.21 Hz,1H) 7.50 (d, J=2.57 Hz, 1H) 7.60 (d, J=2.57 Hz, 1H) 7.65 (dd, J=8.46,1.47 Hz, 1H) 7.73 (d, J=1.84 Hz, 1H) 7.91-8.01 (m, 3H) 8.09 (s, 3H)10.04 (s, 1H) 10.40 (s, 1H).

Example 21 Preparation of ethyl3-(3-(3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido)naphthalen-2-yl)phenyl)ureido)propanoate

Part A. Preparation of ethyl3-(3-(3-tert-butyl-5-iodo-4-methoxyphenyl)ureido)propanoate

3-tert-Butyl-5-iodo-4-methoxyaniline (305 mg, 1 mmol) and ethyl3-isocyanatopropionate were reacted in the same manner as Example 15Part A and purified on an Isco 40 g silica cartridge eluting with ethylacetate/hexane (0% to 25%) to give the title compound (373 mg, 83%).

Part B. Preparation of ethyl3-(3-(3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido)naphthalen-2-yl)phenyl)ureido)propanoate

The product from Part A (179 mg, 0.40 mmol) was reacted in the samemanner as Example 1 Part B at 50° C. for 18 hours to give a solid thatwas triturated with 1:1 hexane/ethyl acetate and collected by filtrationto give the title compound. m.p.>300° C.; ¹H NMR (300 MHz, DMSO-d₆) δppm 1.19 (t, J=7.17 Hz, 3H) 1.39 (s, 9H) 2.44-2.54 (m, 2H) 3.08 (s, 3H)3.14 (s, 3H) 3.28-3.34 (m, 2H) 4.08 (q, J=6.99 Hz, 2H) 6.15 (t, J=5.88Hz, 1H) 7.22 (d, J=2.57 Hz, 1H) 7.37-7.46 (m, 2H) 7.64 (dd, J=8.46, 1.47Hz, 1H) 7.72 (d, J=1.84 Hz, 1H) 7.90 (d, J=8.46 Hz, 1H) 7.94 (s, 1H)7.97 (d, J=9.19 Hz, 1H) 8.54 (s, 1H) 10.01 (s, 1H).

Example 22 Preparation ofN-(6-(3-tert-butyl-5-(3-ethylureido)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)-3-(2-chloroethyl)urea

3-tert-Butyl-5-iodo-4-methoxyaniline (305 mg, 1 mmol) and ethylisocyanate were reacted in the same manner as Example 15 Part A to givethe title compound.

Part B. Preparation ofN-(6-(3-tert-butyl-5-(3-ethylureido)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product from Part A (113 mg, 0.30 mmol) was reacted in the samemanner as Example 1 Part B for 72 hours. The product was triturated in 5mL of methanol and collected by filtration to give the title compound.mp>300° C.; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.04 (t, J=7.17 Hz, 3H) 1.39(s, 9H) 3.03-3.12 (m, 2H) 3.08 (s, 3H) 3.14 (s, 3H) 6.00 (t, J=5.52 Hz,1H) 7.23 (d, J=2.94 Hz, 1H) 7.41 (dd, J=8.82, 2.21 Hz, 1H) 7.44 (d,J=2.57 Hz, 1H) 7.64 (dd, J=8.64, 1.65 Hz, 1H) 7.72 (d, J=1.84 Hz, 1H)7.91 (d, J=8.82 Hz, 1H) 7.94 (s, 1H) 7.97 (d, J=8.82 Hz, 1H) 8.38 (s,1H) 10.00 (s, 1H).

Example 23 Preparation of tert-butyl3-(3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido)naphthalen-2-yl)phenylamino)-3-oxopropylcarbamate

Part A. Preparation of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)-3-(2-chloroethyl)urea

3-tert-Butyl-5-iodo-4-methoxyaniline (305 mg, 1 mmol) andN-(tert-butoxycarbonyl)-1-alanine (189 mg, 1.000 mmol) were reacted inthe same manner as Example 19 Part A for 24 hours. The crude product waspurified on an Isco 12 g silica cartridge eluting with 3% methanol indichloromethane to give the title compound.

Part B. Preparation of tert-butyl3-(3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido)naphthalen-2-yl)phenylamino)-3-oxopropylcarbamate

The product from Part A (100 mg, 0.21 mmol) was reacted in the samemanner as Example 1 Part B for 16 hours. The crude product wastriturated in dichloromethane to give title compound as a solid that wascollected and dried. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.37 (s, 9H) 1.40(s, 9H) 2.44 (t, J=7.17 Hz, 2H) 3.08 (s, 3H) 3.16 (s, 3H) 3.17-3.25 (m,2H) 6.85 (t, J=5.70 Hz, 1H) 7.41 (dd, J=8.82, 2.21 Hz, 1H) 7.47 (d,J=2.57 Hz, 1H) 7.59-7.73 (m, 3H) 7.92 (d, J=10.66 Hz, 1H) 7.94 (s, 1H)7.97 (d, J=8.82 Hz, 1H) 9.90 (s, 1H) 10.01 (s, 1H).

Example 24 Preparation of3-amino-N-(3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido)naphthalen-2-yl)phenyl)propanamide

The product from Example 23 (60 mg, 0.105 mmol) was reacted in the samemanner as Example 2 Part C to give the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.40 (s, 9H) 2.68 (t, J=6.62 Hz, 2H) 3.02-3.13 (m, 2H)3.09 (s, 3H) 3.17 (s, 3H) 7.42 (dd, J=8.82, 2.21 Hz, 1H) 7.50 (d, J=2.57Hz, 1H) 7.60-7.76 (m, 5H) 7.86-8.04 (m, 3H) 10.03 (s, 1H) 10.13 (s, 1H).

Example 25 Preparation ofN-(6-(3-tert-butyl-2-methoxy-5-(2-oxooxazolidin-3-yl)phenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of2-chloroethyl-3-tert-butyl-5-iodo-4-methoxyphenylcarbamate

To a solution of 3-tert-butyl-5-iodo-4-methoxyaniline (0.305 g, 1.0mmol) in dichloromethane (5.00 mL) was added 2-chloroethyl chloroformate(0.143 g, 1.000 mmol) and triethylamine (0.279 mL, 2.0 mmol) to give asolution. The mixture was stirred for 3 hours and concentrated to givethe title compound that was used without purification.

Part B. Preparation of3-(3-tert-butyl-5-iodo-4-methoxyphenyl)oxazolidin-2-one

The product from Part A (412 mg, 1 mmol) in ethanol (5 mL) was treatedwith sodium ethoxide (681 mg, 2.100 mmol) and heated at 60° C. for 2hours, cooled and neutralized to pH 7 with 1 M HCl. The mixture wasdiluted into water and extracted with ethyl acetate. The organics werecombined, washed with brine, dried (Na₂SO₄) and concentrated. Theresidue was purified on an Isco 12 g silica cartridge eluting with 2:1hexane/ethyl acetate to give the title compound.

Part C. Preparation ofN-(6-(3-tert-butyl-2-methoxy-5-(2-oxooxazolidin-3-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part B (94 mg, 0.25 mmol) was reacted in the samemanner as Example 1 Part B for 16 hours. The crude oil was purified on a12 g Isco silica cartridge eluting with 2.5% methanol indichloromethane. The desired fractions were combined and purified asecond time on a 12 g Isco silica cartridge eluting with 3:2hexane/ethyl acetate to give the title compound. mp 216-218° C.; ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.42 (s, 9H) 3.08 (s, 3H) 3.18 (s, 3H) 4.11 (t,J=7.91 Hz, 2H) 4.42 (t, J=7.91 Hz, 2H) 7.38 (d, J=2.57 Hz, 1H) 7.42 (dd,J=8.82, 2.21 Hz, 1H) 7.57 (d, J=2.57 Hz, 1H) 7.67 (dd, J=8.46, 1.84 Hz,1H) 7.73 (d, J=1.84 Hz, 1H) 7.93 (d, J=8.46 Hz, 1H) 7.96-8.00 (m, 2H)10.03 (s, 1H).

Example 26 Preparation ofN-(6-(3-tert-butyl-2-methoxy-5-(2-oxotetrahydropyrimidin-1(2H)-yl)phenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)-3-(3-chloropropyl)urea

3-tert-Butyl-5-iodo-4-methoxyaniline (305 mg, 1 mmol) and ethyl3-chloropropyl isocyanate (0.103 mL, 1.000 mmol) were reacted in thesame manner as Example 15 Part A to give the title compound which wasused without purification.

Part B. Preparation of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)tetrahydropyrimidin-2(1H)-one

The crude product from Part A (425 mg, 1 mmol) in tetrahydrofuran (2 mL)was treated with potassium tert-butoxide (2.200 mL, 2.200 mmol), stirred18 hours and partitioned between ethyl acetate and 1 M HCl. The ethylacetate layer was washed with saturated NaHCO₃, H₂O, and brine. Theorganic layer was dried (Na₂SO₄), filtered and concentrated in vacuo.The crude product was purified on an Isco 12 g silica cartridge elutingwith 4:1 hexane/ethyl acetate to give the title compound.

Part C. Preparation ofN-(6-(3-tert-butyl-2-methoxy-5-(2-oxotetrahydropyrimidin-1(2H)-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part B (116 mg, 0.30 mmol) was reacted in the samemanner as Example 1 Part B for 18 hours, giving the title compound.mp>300° C.; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.40 (s, 9H) 1.88-1.98 (m,2H) 3.07 (s, 3H) 3.19 (s, 3H) 3.19-3.27 (m, 2H) 3.61-3.66 (m, 2H) 6.51(s, 1H) 7.17 (q, J=2.70 Hz, 2H) 7.40 (dd, J=9.01, 2.02 Hz, 1H) 7.66 (dd,J=8.46, 1.47 Hz, 1H) 7.71 (d, J=1.84 Hz, 1H) 7.89-7.99 (m, 3H) 10.01 (s,1H).

Example 27 Preparation ofN-(6-(3-tert-butyl-2-methoxy-5-(2-oxoimidazolidin-1-yl)phenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)-3-(2-chloroethyl)urea

3-tert-Butyl-5-iodo-4-methoxyaniline (305 mg, 1 mmol) and ethyl2-chloroethyl isocyanate (0.085 mL, 1.000 mmol) were reacted in the samemanner as Example 15 Part A to give the title compound which was usedwithout purification.

Part B. Preparation of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)imidazolidin-2-one

The crude product from Part A (411 mg, 1 mmol) was reacted in the samemanner as Example 26 Part B to give crude product which was purified onan Isco 12 g silica cartridge eluting with 4:1 hexane/ethyl acetate togive the title compound.

Part C. Preparation ofN-(6-(3-tert-butyl-2-methoxy-5-(2-oxoimidazolidin-1-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part B (112 mg, 0.30 mmol) was reacted in the samemanner as Example 1 Part B for 72 hours. The crude product wastriturated in 1:1 ethyl acetate/methanol (5 mL) and the solid collectedby filtration to give the title compound. m.p. 284-286° C.; ¹H NMR (300MHz, DMSO-d₆) δ ppm 1.41 (s, 9H) 3.08 (s, 3H) 3.15 (s, 3H) 3.34-3.43 (m,2H) 3.85-3.93 (m, 2H) 6.87 (s, 1H) 7.36 (d, J=2.57 Hz, 1H) 7.41 (dd,J=8.82, 2.21 Hz, 1H) 7.56 (d, J=2.57 Hz, 1H) 7.66 (dd, J=8.46, 1.47 Hz,1H) 7.72 (d, J=1.84 Hz, 1H) 7.92 (d, J=8.82 Hz, 1H) 7.97 (d, J=8.09 Hz,2H) 10.01 (s, 1H).

Example 28 Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of 5-bromo-2,4-di-tert-butoxypyrimidine

The title compound was prepared from 5-bromo-2,4-dichloropyrimidineaccording to the procedure of Organic Letters 8(18), 4121 (2006). ¹H NMR(300 MHz, CDCl₃) δ ppm 1.60 (s, 9H) 1.65 (s, 9H) 8.25 (s, 1H).

Part B. Preparation of 2,4-di-tert-butoxypyrimidin-5-ylboronic acid

The title compound was prepared from the product of Part A according tothe procedure of Chemica Scripta 26, 305 (1986). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.56 (s, 9H) 1.59 (s, 9H) 7.60 (s, 2H) 8.35 (s, 1H).

Part C. Preparation of2,4-di-tert-butoxy-5-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine

A nitrogen-purged flask was charged with1-tert-butyl-3,5-diiodo-2-methoxybenzene (100 mg, 0.240 mmol) andanhydrous 1,2-dimethoxyethane (0.8 mL), and the solution sparged withnitrogen for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (8.33mg, 7.2 μmol) was and the mixture was sparged with nitrogen for 10minutes. The product of Part B (70.9 mg, 0.264 mmol) and 1 M aqueousNaHCO₃ (0.6 mL, 0.6 mmol) were added, and the mixture was heated atreflux (oil bath temperature 100° C.) for 2 hours. The reaction mixturewas cooled to room temperature, diluted with ethyl acetate (50 mL), andwashed with H₂O (25 mL) and brine (25 mL), dried (MgSO₄), filtered, andconcentrated in vacuo to give crude product which was purified by silicagel flash chromatography eluting with 1% ethyl acetate/dichloromethaneto give the title compound. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.41 (s, 9H)1.65 (s, 18H) 3.92 (s, 3H) 7.45 (s, 1H) 7.82 (s, 1H) 8.18 (s, 1H).

Part D. Preparation ofN-(6-(3-tert-butyl-5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product of Part C (84.2 mg, 0.164 mmol) andN-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)methanesulfonamide (74.2 mg, 0.214 mmol)were reacted in the same manner as Example 1 Part B at 50° C. for 2hours. The crude product was purified by silica gel flash chromatographyeluting with 10% ethyl acetate/dichloromethane to give the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.45 (s, 9H) 1.59 (s, 9H) 1.62(s, 9H) 3.08 (s, 3H) 3.23 (s, 3H) 7.39-7.45 (m, 2H) 7.51 (d, J=2.21 Hz,1H) 7.70-7.76 (m, 2H) 7.93 (dd, J=8.82, 2.94 Hz, 2H) 8.06 (d, J=0.74 Hz,1H) 8.40 (s, 1H) 10.01 (s, 1H).

Part E. Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

A solution of the product of Part D (40 mg, 0.066 mmol) in methanol (0.7mL) and 6 N HCl (0.35 mL) was stirred at 25° C. for 2 hours. During thecourse of the reaction, the product precipitated out of solution. Themixture was vacuum filtered and the collected solids were washed withsmall volumes of methanol and dried in vacuo. The crude product wasdissolved in 1:1 (v/v) methanol/dimethyl sulfoxide (1 mL) and purifiedby RP-C₁₈ HPLC (Waters Prep LC, 25 mm Module with Nova Pak HR C₁₈ 6 μm25×100 mm Prep Pak cartridge) eluting with a 30 minute gradient of 90:100.1% trifluoroacetic acid in H₂O/acetonitrile to 25:75 0.1%trifluoroacetic acid in H₂O/acetonitrile at 10 mL/minute. This gave thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.42 (s, 9H) 3.08 (s,3H) 3.20 (s, 3H) 7.38-7.50 (m, 3H) 7.67-7.71 (m, 1H) 7.71 (dd, J=5.52,1.84 Hz, 2H) 7.92 (d, J=8.82 Hz, 1H) 7.97 (d, J=9.19 Hz, 1H) 8.01 (s,1H) 10.01 (s, 1H) 11.12 (dd, J=4.04, 1.10 Hz, 1H) 11.22 (s, 1H).

Example 29 Preparation ofN-(6-(3-tert-butyl-2-methoxy-5-(2-oxopyrrolidin-1-yl)phenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrrolidin-2-one

In a 5 mL microwave tube under N₂ flush were added1-tert-butyl-3,5-diiodo-2-methoxybenzene (208 mg, 0.5 mmol),2-pyrrolidone (0.092 mL, 1.200 mmol), potassium phosphate (223 mg, 1.050mmol), (+/−)-trans-1,2-diaminocyclohexane (0.012 mL, 0.100 mmol) andcopper(I) iodide (2.381 mg, 0.013 mmol) in dioxane (2 mL). The tube wassealed, sparged with N₂ for 10 minutes, heated by microwave irradiationat 110° C. for 1 hour, cooled and partitioned between ethyl acetate andwater adjusting the pH to 1 with HCl. The aqueous layer was extractedwith ethyl acetate. The organics were combined, washed with H₂O, andbrine. The organic was dried (Na₂SO₄), filtered, and stirred for 0.5hours with 3-mercaptopropyl functionalized silica, filtered andconcentrated. The crude product was purified on an Isco 12 g silicacartridge eluting with 4:1 hexane/ethyl acetate to give the titlecompound.

Part B. Preparation ofN-(6-(3-tert-butyl-2-methoxy-5-(2-oxopyrrolidin-1-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part A (0.09 g, 0.241 mmol) andN-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-yl)methanesulfonamide (0.092 g, 0.265 mmol)were reacted in the same manner as Example 1 Part B at 50° C. for 18hours giving crude product which was purified on an Isco 12 g silicacartridge eluting with methanol/dichloromethane (0% to 2%) to give thetitle compound. mp 229-230° C.; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.41 (s,9H) 2.00-2.14 (m, 2H) 2.38-2.50 (m, 2H) 3.08 (s, 3H) 3.18 (s, 3H) 3.87(t, J=6.99 Hz, 2H) 7.41 (dd, J=8.82, 2.21 Hz, 1H) 7.46 (d, J=2.57 Hz,1H) 7.60-7.69 (m, 2H) 7.72 (d, J=1.84 Hz, 1H) 7.84-8.01 (m, 3H) 10.02(s, 1H).

Example 30 Preparation ofN-(6-(3-tert-butyl-2-methoxy-5-(2-oxopyridin-1(2H)-yl)phenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyridin-2(1H)-one

In a 20 mL microwave tube were added pyridin-2-ol (190 mg, 2 mmol),copper(I) iodide (76 mg, 0.400 mmol),1-tert-butyl-3,5-diiodo-2-methoxybenzene (998 mg, 2.400 mmol), potassiumphosphate (849 mg, 4.00 mmol) and N,N′-dimethylethylenediamine (0.086mL, 0.800 mmol) in dioxane (10 mL). The tube was sealed and the mixturewas sparged with N₂ for 10 minutes and heated in an oil bath at 110° C.for 16 hours. The mixture was cooled and partitioned into ethyl acetate.The organic layer was washed with saturated NaHCO₃, brine, dried(Na₂SO₄), filtered and the filtrate was treated with 3-mercaptopropylfunctionalized silica gel, filtered through diatomaceous earth andconcentrated in vacuo to give crude product which was purified on anIsco 12 g silica cartridge eluting with 3:2 hexane/ethyl acetate to givethe title compound.

Part B. Preparation ofN-(6-(3-tert-butyl-2-methoxy-5-(2-oxopyridin-1(2H)-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part A (153 mg, 0.40 mmol) was reacted in the samemanner as Example 1 Part B at 50° C. for 18 hours giving a crude productwhich was purified on an Isco 12 g silica cartridge eluting with ethylacetate/hexane (10% to 100%) to give the title compound. m.p. 258-260°C.; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.43 (s, 9H) 3.08 (s, 3H) 3.26 (s,3H) 6.26-6.35 (m, 1H) 6.48 (d, J=8.82 Hz, 1H) 7.27 (d, J=2.57 Hz, 1H)7.33 (d, J=2.57 Hz, 1H) 7.42 (dd, J=8.82, 1.84 Hz, 1H) 7.45-7.54 (m, 1H)7.68-7.81 (m, 3H) 7.96 (t, J=8.27 Hz, 2H) 8.04 (s, 1H) 10.03 (s, 1H).

Example 31 Preparation ofN-(6-(5-benzoyl-3-tert-butyl-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of1-tert-butyl-3-iodo-2-methoxy-5-(1-phenylvinyl)benzene

A solution of 1-tert-butyl-3,5-diiodo-2-methoxybenzene (4.94 g, 11.87mmol) in dimethoxyethane (50 mL) and water (30 mL) was treated with1-phenylvinylboronic acid (2.283 g, 15.43 mmol),tetrakis(triphenylphosphine)palladium(0) (0.686 g, 0.593 mmol) andsodium bicarbonate (2.492 g, 29.7 mmol) followed by heating at 100° C.for 3 hours. 1 N HCl was added and the mixture was extracted with ethylacetate, then dried (Na₂SO₄), filtered and concentrated in vacuo to givecrude product which was purified by silica gel flash chromatographyeluting with 50:1 hexanes/ethyl acetate to give the title compound.

Part B. Preparation of(3-tert-butyl-5-iodo-4-methoxyphenyl)(phenyl)methanone

The product from Part A (1.10 g, 2.80 mmol) was dissolved in acetone andcooled to −78° C., then potassium permanganate (4.43 g, 28.0 mmol) wasadded and the resultant solution stirred at −78° C. for 2 hours. Thesolution was slowly warmed to room temperature and stirred for anadditional 3 hours. Isopropanol (10 mL) and dichloromethane (25 mL) wereadded, and the mixture was stirred for 15 minutes and then filtered. Thefiltrate was concentrated in vacuo to give the title compound.

Part C. Preparation ofN-(6-(5-benzoyl-3-tert-butyl-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product from Part B (0.115 g, 0.292 mmol) was reacted in the samemanner as Example 1 Part B at 50° C. for 24 hours to give crude productwhich was purified on an Isco 12 g silica cartridge eluting with hexanesin ethyl acetate to provide the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.44 (s, 9H), 3.08 (s, 3H), 3.30 (s, 3H), 7.42 (dd,J=8.8, 2.2 Hz, 1H), 7.65 (m, 2H), 7.72 (m, 2H), 7.79 (m, 3H), 7.85 (m,1H), 7.98 (m, 2H), 10.03 (s, 1H).

Example 32 Preparation of(E)-N-(4-(5-benzoyl-3-tert-butyl-2-methoxystyryl)phenyl)methanesulfonamide

(E)-4-(Methylsulfonamido)styryl boronic acid (0.673 g, 0.279 mmol) andthe product from Example 31 Part B (0.100 g, 0.254 mmol) were reacted inthe same manner as Example 1 Part C at 60° C. for 24 hours to give crudeproduct which was purified on an Isco 12 g silica cartridge eluting withhexanes in ethyl acetate to provide the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.39 (s, 9H), 3.01 (s, 3H), 3.84 (s, 3H), 7.16 (d, J=16.5Hz, 1H), 7.22 (d, J=8.5 Hz, 2H), 7.30 (d, J=16.5 Hz, 1H), 7.62 (m, 6H),7.78 (m, 2H), 7.91 (d, J=2.2 Hz, 1H), 9.85 (s, 1H).

Example 33 Preparation ofN-(6-(2-amino-3-tert-butyl-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of 2-tert-butyl-4-iodoaniline

In a 500 mL round-bottomed flask was combined 2-tert-butylaniline (7.46g, 50 mmol) and sodium bicarbonate (7.56 g, 90 mmol) in water (50 mL).The mixture was cooled to 0° C. and iodine (12.69 g, 50.0 mmol) wasadded portion-wise over 20 minutes. The mixture was stirred for 16 hoursat room temperature, partitioned between ethyl acetate and 10% aqueoussodium thiosulfate and stirred vigorously for 20 minutes. The ethylacetate layer was washed with brine, dried (Na₂SO₄), filtered andconcentrated in vacuo to give a dark oil that was purified on an Isco120 g silica cartridge eluting with ethyl acetate/hexane (0% to 10%) togive the title compound.

Part B. Preparation of2-tert-butyl-4-(2,4-di-tert-butoxypyrimidin-5-yl)aniline

The product from Part A (138 mg, 0.5 mmol) and the product from Example28 Part B (134 mg, 0.500 mmol) were reacted in the same manner asExample 1 Part B for 1 hour to give crude product which was purified onan Isco 12 g silica cartridge eluting with 15% ethyl acetate in hexaneto give the title compound.

Part C. Preparation of2-bromo-6-tert-butyl-4-(2,4-di-tert-butoxypyrimidin-5-yl)aniline

The product from Part B (160 mg, 0.431 mmol) and1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (62.2 mg, 0.217 mmol)were combined in chloroform (4 mL). The reaction mixture was stirred for1 hour, washed with sodium thiosulfate, brine, dried (Na₂SO₄), filteredand concentrated in vacuo to give crude product which was purified on anIsco 12 g silica cartridge eluting with 9:1 hexane/ethyl acetate to givethe title compound.

Part D. Preparation ofN-(6-(2-amino-3-tert-butyl-5-(2,4-di-tert-butoxypyrimidin-5-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part C (80 mg, 0.178 mmol) andN-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-yl)methanesulfonamide(61.7 mg, 0.178 mmol) were reacted in the same manner as Example 1 PartC at 50° C. for 16 hours to give crude product which was purified on anIsco 12 g silica cartridge eluting with methanol/dichloromethane (0% to3%) to give the title compound.

Part E. Preparation ofN-(6-(2-amino-3-tert-butyl-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part D (77 mg, 0.130 mmol) was reacted in the samemanner as Example 1 Part D giving a solid that was washed repeatedlywith diethyl ether and dried to constant mass giving the title compound.m.p. 254-260° C.; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.43 (s, 9H) 3.07 (s,3H) 7.18 (d, J=1.84 Hz, 1H) 7.38-7.46 (m, 2H) 7.51-7.59 (m, 2H) 7.74 (d,J=2.21 Hz, 1H) 7.86-7.98 (m, 3H) 10.03 (s, 1H) 11.00 (dd, J=5.88, 1.84Hz, 1H) 11.13 (d, J=1.84 Hz, 1H).

Example 34 Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-iodophenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation ofN-(6-(3-tert-butyl-5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-iodophenyl)naphthalen-2-yl)methanesulfonamide

To a 10 mL round-bottomed flask was added the product from Example 33Part D (59 mg, 0.100 mmol), tert-butyl nitrite (0.012 mL, 0.100 mmol),copper(I) iodide (19.02 mg, 0.100 mmol), sodium iodide (14.97 mg, 0.100mmol) and iodine (12.67 mg, 0.050 mmol) in 1,2-dimethoxyethane (2 mL).The mixture was heated at 60° C. for 2 hours. The reaction mixture waspartitioned with ethyl acetate and 10% sodium thiosulfate. The organiclayer was washed with brine, dried (Na₂SO₄), filtered and concentratedin vacuo to give crude product which was purified by silica gel flashchromatography eluting with ethyl acetate/hexane (5% to 20%) to give thetitle compound.

Part B. Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-iodophenyl)naphthalen-2-yl)methanesulfonamide

The product from Part A (30 mg, 0.043 mmol) was reacted in the samemanner as Example 3 Part B to give the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.61 (s, 9H) 3.07 (s, 3H) 7.39 (m, 3H) 7.69 (m, 3H) 7.80(s, 1H) 7.88 (d, J=8.82 Hz, 1H) 7.93 (d, J=8.82 Hz, 1H) 10.00 (s, 1H)11.22 (s, 1H) 11.27 (s, 1H).

Example 35N-(6-(3-tert-butyl-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-vinylphenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation ofN-(6-(3-tert-butyl-5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-vinylphenyl)naphthalen-2-yl)methanesulfonamide

To a 5 mL microwave tube was added the product from Example 34 Part A(210 mg, 0.3 mmol), tributyl(vinyl)stannane (0.175 mL, 0.600 mmol),potassium phosphate (134 mg, 0.63 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (8.77 mg,0.030 mmol) and tris(dibenzylideneacetone)dipalladium(0) (13.74 mg,0.015 mmol) in dimethyl sulfoxide (3 mL). The mixture was purged withnitrogen for 5 minutes and microwaved at 100° C. for 1 hour. Thereaction mixture was partitioned with ethyl acetate and 0.1 M HCl. Theorganic layer was washed with saturated NaHCO₃, brine, dried (Na₂SO₄),filtered and the filtrate treated with 3-mercaptopropyl functionalizedsilica gel, filtered and concentrated in vacuo to give crude productwhich was purified by silica gel flash chromatography eluting with ethylacetate/hexane (10% to 20%) to give the title compound.

Part B. Preparation ofN-(6-(3-tert-butyl-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-vinylphenyl)naphthalen-2-yl)methanesulfonamide

The product from Part A (30 mg, 0.050 mmol) was reacted in the samemanner as Example 3 Part B to give the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.43 (s, 9H) 3.05 (s, 3H) 4.63 (dd, J=17.65, 2.21 Hz, 1H)5.12 (dd, J=11.21, 2.02 Hz, 1H) 7.16 (dd, J=17.83, 11.21 Hz, 1H) 7.37(m, 3H) 7.60 (d, J=1.84 Hz, 1H) 7.67 (d, J=1.84 Hz, 1H) 7.74 (m, 2H)7.78 (d, J=8.82 Hz, 1H) 7.87 (d, J=9.19 Hz, 1H) 9.95 (s, 1H) 11.15 (s,1H) 11.23 (s, 1H).

Example 36N-(6-(3-tert-butyl-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-ethylphenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation ofN-(6-(3-tert-butyl-5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-ethylphenyl)naphthalen-2-yl)methanesulfonamide

To a 100 mL round-bottomed flask was added the product from Example 35Part A (132 mg, 0.219 mmol), 10% palladium on carbon (20 mg, 0.019 mmol)and methanol (10 mL). The mixture was hydrogenated for 24 hours,filtered and concentrated in vacuo to give crude product which waspurified by silica gel flash chromatography eluting with ethylacetate/hexane (10% to 20%) to give the title compound.

Part B.N-(6-(3-tert-butyl-5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-ethylphenyl)naphthalen-2-yl)methanesulfonamide

The product from Part A (92 mg, 0.152 mmol) was reacted in the samemanner as Example 3 Part B to give the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 0.69 (t, J=7.17 Hz, 3H) 1.46 (s, 9H) 2.96 (q, J=7.17 Hz,2H) 3.07 (s, 3H) 7.19 (d, J=1.84 Hz, 1H) 7.41 (dd, J=8.82, 2.21 Hz, 1H)7.46 (dd, J=8.46, 1.84 Hz, 1H) 7.54 (d, J=1.84 Hz, 1H) 7.65 (s, 1H) 7.73(d, J=1.84 Hz, 1H) 7.81 (s, 1H) 7.89 (d, J=8.82 Hz, 1H) 7.93 (d, J=9.19Hz, 1H) 9.98 (s, 1H) 11.10 (s, 1H) 11.19 (s, 1H).

Example 37 Preparation ofN-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(perfluoroethyl)phenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation ofN-(6-(2-methoxy-5-nitro-3-(perfluoroethyl)phenyl)naphthalen-2-yl)methanesulfonamide

1-Bromo-2-methoxy-5-nitro-(3-perfluoroethyl)benzene (0.25 g, 0.630 mmol)andN-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-yl)methanesulfonamide(0.219 g, 0.630 mmol) were reacted in the same manner as Example 1 PartB at 50° C. for 16 hours to give crude product which was purified on anIsco 12 g silica cartridge eluting with 3:1 hexane/ethyl acetate to givethe title compound.

Part B. Preparation ofN-(6-(5-amino-2-methoxy-3-(perfluoroethyl)phenyl)naphthalen-2-yl)methanesulfonamide

A mixture of the product from Part A (0.27 g, 0.551 mmol), iron (0.154g, 2.75 mmol), and ammonium chloride (0.044 g, 0.826 mmol) in a solventmixture of tetrahydrofuran, ethanol, and water 3:3:1 (15 mL) was heatedat 95-100° C. for 2 hours. The reaction mixture was filtered through aplug of diatomaceous earth and rinsed repeatedly with tetrahydrofuran.The filtrate was concentrated in vacuo and the residue was dissolved inethyl acetate, washed with water, brine, dried (Na₂SO₄), filtered andconcentrated in vacuo to give the title compound that was used withoutpurification.

Part C. Preparation ofN-(6-(5-iodo-2-methoxy-3-(perfluoroethyl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part B (0.25 g, 0.543 mmol) was reacted in the samemanner as Example 34 Part A for 3 hours to give material that waspurified on an Isco 40 g silica cartridge eluting with ethylacetate/hexane (5% to 30%) to give the title compound.

Part D. Preparation ofN-(6-(5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxy-3-(perfluoroethyl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part C (0.13 g, 0.228 mmol) and the product fromExample 28 Part B (0.064 g, 0.239 mmol) were reacted in the same manneras Example 1 Part B at 50° C. for 16 hours to give crude product whichwas purified on an Isco 40 g silica cartridge eluting with 15% ethylacetate in hexane to give the title compound.

Part E. Preparation ofN-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(perfluoroethyl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part D (0.10 g, 0.150 mmol) was reacted in the samemanner as Example 1 Part D to give crude product which was purified onan Isco 4 g silica cartridge eluting with ethyl acetate to give a lightyellow oil that was triturated in 95:5 dichloromethane/methanol to givethe title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.09 (s, 3H) 3.28(s, 3H) 7.43 (dd, J=8.82, 1.84 Hz, 1H) 7.67-7.77 (m, 2H) 7.85-8.03 (m,5H) 8.10 (s, 1H) 10.10 (s, 1H) 11.28 (s, 1H) 11.36 (s, 1H).

Example 38 Preparation ofN-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-(furan-3-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of 2-iodo-4-nitrophenol

2-Iodophenol (5.94 g, 27.0 mmole) was dissolved in acetonitrile (54 mL)and cooled in an ice bath. A solution of 1:1 v/v of glacial aceticacid/70% nitric acid was added dropwise and the solution was stirred 30minutes in the ice bath. The reaction mixture was poured onto 500 g ofice water and extracted with dichloromethane. The combined organicextracts were washed with water and brine, dried (MgSO₄), filtered andconcentrated in vacuo leaving a residue which was purified by silica gelflash chromatography eluting with ethyl acetate/hexane (5% to 50%) togive the title compound.

Part B. Preparation of 2-bromo-6-iodo-4-nitrophenol

Product from Part A (3.54 g, 13.36 mmole) was dissolved in acetonitrile(60 mL) and treated with 1,3-dibromo-5,5-dimethylhydantoin (2.1 g, 7.35mmole) and stirred at room temperature for 15 hours. The resultingreaction mixture was concentrated in vacuo to a residue which wasdissolved in dichloromethane, washed with water, 10% NaS₂O₃ solution,brine, dried (MgSO₄), filtered and concentrated in vacuo leaving a solidwhich was purified by silica gel flash chromatography eluting with ethylacetate/hexane (5% to 50%) to give the title compound

Part C. Preparation of 1-bromo-3-iodo-2-methoxy-5-nitrobenzene

Product from Part B (1.92 g, 5.58 mmole) was reacted in the same manneras Example 1 Part A for 20 hours giving crude product which was purifiedby silica gel flash chromatography eluting with ethyl acetate/hexane (0%to 50%) to give the title compound.

Part D. Preparation ofN-(6-(3-bromo-2-methoxy-5-nitrophenyl)naphthalen-2-yl)methanesulfonamide

Product from Part C (1.26 g, 3.52 mmole) andN-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)methanesulfonamide(1.22 g, 3.52 mmole) were reacted in the same manner as Example 1 Part Bfor 96 hours giving crude product which was purified by silica gel flashchromatography eluting with methanol/dichloromethane (0% to 5%) givingthe title compound.

Part E. Preparation ofN-(6-(3-(furan-3-yl)-2-methoxy-5-nitrophenyl)naphthalen-2-yl)methanesulfonamide

Product from Part D (0.1 g, 0.226 mmole), furan-3-ylboronic acid (32 mg,0.282 mmole), 2 μl sodium carbonate (0.52 mL) andtetrakis(triphenylphosphine)palladium(0) (13 mg, 0.011 mmol) werecombined and dissolved in 1,2-dimethoxyethane (2.3 mL) purged with N₂and heated at 80° C. for 18 hours. The reaction mixture was diluted with50 mL of ethyl acetate, washed with 10% HCl, 10% NaHCO₃, brine, dried(Na₂SO₄), filtered and concentrated in vacuo giving the title compound.

Part F. Preparation ofN-(6-(5-amino-3-(furan-3-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product from Part E (0.101 g, 0.230 mmol) was reacted in the samemanner as Example 37 Part B at 80° C. for 1 hour giving crude productwhich was partitioned between water and dichloromethane and the aqueousphase was extracted with dichloromethane, the organics combined, dried(MgSO₄), filtered and concentrated in vacuo to provide the titlecompound which was used as isolated in the next step.

Part G. Preparation ofN-(6-(3-(furan-3-yl)-5-iodo-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product from Part F (0.10 g, 0.247 mmol) was reacted in the samemanner as Example 34 Part A for 1 hour giving crude residue which waspurified by silica gel flash chromatography eluting withdichloromethane/hexane to give a mixture of 5-iodo and 5-protiocompounds suitable for use as isolated in the next step.

Part H. Preparation ofN-(6-(5-(2,4-di-tert-butoxypyrimidin-5-yl)-3-(furan-3-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product mixture from Part G (0.039 g) and product from Example 28Part B (0.021 g, 0.077 mmol) were reacted in the same manner as Example1 Part B for 18 hours giving crude product which was purified by silicagel flash chromatography eluting with dichloromethane/hexane to give thetitle compound.

Part I. Preparation ofN-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-(furan-3-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product from Part H (0.027 g, 0.044 mmol) was reacted in the samemanner as Example 1 Part D to give title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 3.09 (s, 3H) 3.25 (s, 3H) 7.07 (d, J=1.47 Hz, 1H) 7.42(dd, J=8.82, 2.21 Hz, 1H) 7.57 (d, J=2.21 Hz, 1H) 7.69-7.89 (m, 5H) 7.93(d, J=8.82 Hz, 1H) 7.98 (d, J=8.82 Hz, 1H) 8.08 (s, 1H) 8.21 (s, 1H)10.02 (s, 1H) 11.23 (d, J=5.88 Hz, 1H) 11.28 (s, 1H).

Example 39 Preparation ofN-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(thiophen-2-yl)phenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation ofN-(6-(5-amino-3-bromo-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product from Example 38 Part D (0.10 g, 0.222 mmol) was reacted inthe same manner as Example 38 Part F to give the title compound.

Part B. Preparation ofN-(6-(3-bromo-5-iodo-2-methoxyphenyl)naphthalen-2-yl)methane sulfonamide

The product from Part A (0.094 g, 0.222 mmol) was reacted in the samemanner as Example 38 Part G to give the title compound contaminated withan undetermined amount of the corresponding des-iodo compound.

Part C. Preparation ofN-(6-(3-bromo-5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product from Part B (0.051 g, 0.048 mmol-assume 50% iodo analog) wasreacted in the same manner as Example 38 Part H to give the titlecompound.

Part D. Preparation ofN-(6-(5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxy-3-(thiophen-2-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part C (0.0281 g, 0.045 mmol) as a solution in1,2-dimethoxyethane (1 mL) was combined at room temperature in amicrowave tube with thiophen-2-ylboronic acid (8.01 mg, 0.063 mmol),sodium carbonate, (0.022 g, 0.206 mmol),1,1′-bis(di-tertbutylphosphino)ferrocene palladium dichloride (2.37 mg,0.0036 mmol) and water (100 μL). The tube was sealed and sparged withnitrogen for 5 minutes, then all gas lines were removed and the vesselheated in an oil bath at 55° C. for 18 hours. The contents of the tubewere partitioned between ethyl acetate and brine. The aqueous phase wasextracted with ethyl acetate, the organics combined, dried (MgSO₄) andconcentrated in vacuo to give crude product which was purified by silicagel flash chromatography eluting with ethyl acetate/hexanes to give thetitle compound.

Part E. Preparation ofN-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(thiophen-2-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part D (18.8 mg, 0.030 mmol) was reacted in the samemanner as Example 1 Part D to give the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 3.08 (s, 3H) 3.25 (s, 3H) 7.17 (dd, J=5.15, 3.68 Hz, 1H)7.42 (dd, J=8.82, 2.21 Hz, 1H) 7.56-7.82 (m, 4H) 7.85-8.05 (m, 4H) 8.10(s, 1H) 9.90-10.20 (m, 1H) 11.30 (s, 1H).

Example 40 Preparation ofN-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-(furan-2-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation ofN-(6-(5-(2,4-di-tert-butoxypyrimidin-5-yl)-3-(furan-2-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product from Example 39 Part C (0.0568 g, 0.090 mmol) andfuran-2-ylboronic acid (0.016 g, 0.142 mmol) were reacted in the samemanner as Example 1 Part C at 55° C. for 18 hours to give crude productwhich was purified by silica gel flash chromatography eluting with ethylacetate/hexanes to provide the title compound.

Part B. Preparation ofN-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-(furan-2-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product from Part A (0.049 g, 0.080 mmol) was reacted in the samemanner as Example 1 Part D giving the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 3.09 (s, 3H) 3.30 (s, 3H) 6.66 (dd, J=3.31, 1.84 Hz, 1H)7.04 (d, J=3.31 Hz, 1H) 7.42 (dd, J=8.82, 2.21 Hz, 1H) 7.53 (d, J=2.21Hz, 1H) 7.68-7.88 (m, 4H) 7.91-8.03 (m, 3H) 8.11 (s, 1H) 10.03 (s, 1H)11.17-11.25 (m, 1H) 11.30 (s, 1H).

Example 41 Preparation ofN-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation ofN-(6-(5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Example 39 Part C (0.050 g, 0.080 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.0276 mg, 0.133 mmol) were reacted in the same manner as Example 1Part C to give the title compound.

Part B. Preparation ofN-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part A (0.045 g, 0.072 mmol) was reacted in the samemanner as Example 1 Part D to give the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 3.08 (s, 3H) 3.23 (s, 3H) 3.91 (s, 3H) 7.42 (dd, J=8.82,2.21 Hz, 1H) 7.50 (d, J=2.21 Hz, 1H) 7.69-7.85 (m, 4H) 7.89-8.02 (m, 3H)8.07 (s, 1H) 8.20 (s, 1H) 9.91-10.14 (m, 1H) 11.13-11.23 (m, 1H) 11.27(s, 1H).

Example 42 Preparation ofN-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(5-methylfuran-2-yl)phenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation ofN-(6-(5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxy-3-(5-methylfuran-2-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Example 39 Part C (0.035 g, 0.055 mmol) and4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane (15.72mg, 0.072 mmol) were reacted in the same manner as Example 1 Part C togive the title compound.

Part B. Preparation ofN-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(5-methylfuran-2-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part A (10 mg, 0.016 mmol) was reacted in the samemanner as Example 1 Part D to give the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 2.38 (s, 3H) 3.08 (s, 3H) 3.29 (s, 3H) 6.27 (d, J=2.21Hz, 1H) 6.92 (d, J=2.94 Hz, 1H) 7.42 (dd, J=8.82, 2.21 Hz, 1H) 7.47 (d,J=2.21 Hz, 1H) 7.71-7.81 (m, 3H) 7.88-8.02 (m, 3H) 8.10 (s, 1H)9.89-10.19 (m, 1H) 11.12-11.23 (m, 1H) 11.29 (s, 1H).

Example 43 Preparation ofN-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(thiophen-3-yl)phenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation of 3-bromo-5-iodo-4-methoxyaniline

The product from Example 38 Part C (0.36 g, 1.01 mmol) was reacted inthe same manner as Example 37 Part B at reflux for 90 minutes to givethe title compound.

Part B. Preparation of(E)-1-((3-bromo-5-iodo-4-methoxyphenyl)diazenyl)pyrrolidine

The product from Part A (0.32 g, 1 mmol) was dissolved intetrahydrofuran (5 mL), cooled to 0° C. in an ice bath and concentratedHCl (0.15 mL) was added. The resulting clear yellow solution was treateddropwise with NaNO₂ (93 mg, 1.35 mmol) in 0.3 mL water and the resultingthick solution becomes clear then opaque again over the course of 15minutes stirring in the cold. To this mixture was added pyrrolidine (0.7mL, 8.3 mmole) and the mixture was stirred 15 minutes in an ice bath.The mixture was treated with 100 mL of ethyl acetate, washed with waterand brine, dried (Na₂SO₄), filtered and concentrated in vacuo leaving aresidue which was purified on an Isco 12 g silica cartridge eluting withethyl acetate/hexane (5% to 50%) to give the title compound.

Part C. Preparation of(E)-N-(6-(3-bromo-2-methoxy-5-(pyrrolidin-1-yldiazenyl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part B (0.107 g, 0.26 mmol) andN-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)methanesulfonamide(91 mg, 0.26 mmol) were reacted in the same manner as Example 1 Part Bfor 17 hours to give the title compound.

Part D. Preparation ofN-(6-(3-bromo-5-iodo-2-methoxyphenyl)naphthalen-2-yl)methane sulfonamide

The product from Part C (0.1 g, 0.199 mmol) was dissolved in1,2-dichloroethane (2 mL), I₂ (50 mg, 0.199 mmol) was added and theresulting reaction mixture was heated at 80° C. in a sealed tube for 4hours. The reaction mixture was diluted with 50 mL of dichloromethane,washed with 30% aqueous Na₂S₂O₃ and brine, dried (Na₂SO₄), filtered andconcentrated in vacuo leaving a residue which was purified on an Isco 12g silica cartridge eluting with ethyl acetate/hexane (5% to 80%) to givethe title compound.

Part E. Preparation ofN-(6-(3-bromo-5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

The product from Part D (23 mg, 0.043 mmole) and2,4-di-tert-butoxypyrimidin-5-yl boronic acid (14 mg, 0.052 mmol) werereacted in the same manner as Example 1 Part B for 18 hours to give thetitle compound.

Part F. Preparation ofN-(6-(5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxy-3-(thiophen-3-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part E (25 mg, 0.04 mmole) and thiophen-3-ylboronicacid (6.1 mg, 0.048 mmole) were reacted in the same manner as Example 1Part C at 40° C. for 1 hour, then heated at 50° C. for 1 hour to give aresidue which was purified on an Isco 4 g silica cartridge eluting withmethanol/dichloromethane (1% to 3%) to give the title compound.

Part G. Preparation ofN-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(thiophen-3-yl)phenyl)naphthalen-2-yl)methanesulfonamide

The product from Part F (12 mg, 0.019 mmol) was reacted in the samemanner as Example 3 Part B to give the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 3.07 (s, 3H) 3.20 (s, 3H) 7.41 (dd, J=8.82, 2.21 Hz, 2H)7.51-7.70 (m, 4H) 7.72-7.81 (m, 2H) 7.83-8.03 (m, 4H) 8.07 (s, 1H) 10.02(s, 1H) 11.28 (s, 1H).

Example 44 Preparation ofN-((6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(5-methylfuran-2-yl)phenyl)-1H-inden-3-yl)methyl)methanesulfonamide

Part A. Preparation of(E)-1-((3-bromo-4-methoxy-5-(5-methylfuran-2-yl)phenyl)diazenyl)pyrrolidine

1-((3-Bromo-5-iodo-4-methoxyphenyl)diazenyl)pyrrolidine (0.15 g, 0.366mmol) and 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane(0.076 g, 0.366 mmol), were reacted in the same manner as Example 1 PartB for 18 hours to give crude product which was purified on an Isco 12 gsilica cartridge eluting with ethyl acetate/hexane (0% to 25%) to givethe title compound.

Part B. Preparation of 2-(3-bromo-5-iodo-2-methoxyphenyl)-5-methylfuran

The product from Part A (0.10 g, 0.275 mmol) was reacted in the samemanner as Example 43 Part D using acetonitrile as solvent and heating at100° C. for 2 hours to give crude product which was purified on an Isco12 g silica cartridge eluting with ethyl acetate/hexane (0% to 10%) togive the title compound.

Part C. Preparation of5-(3-bromo-4-methoxy-5-(5-methylfuran-2-yl)phenyl)-2,4-di-tert-butoxypyrimidine

The product from Part B (0.045 g, 0.114 mmol) and the product fromExample 28 Part B (0.032 g, 0.12 mmol) were reacted in the same manneras Example 1 Part B for 18 hours to give crude product which waspurified on an Isco 4 g silica cartridge eluting with ethylacetate/hexane (10% to 20%) to give the title compound.

Part D. Preparation ofN-((6-(5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxy-3-(5-methylfuran-2-yl)phenyl)-1H-inden-3-yl)methyl)methanesulfonamide

The product from Part C (0.035 g, 0.072 mmol) andN-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-inden-3-yl)methyl)methanesulfonamide (0.028 g, 0.079mmol) were reacted in the same manner as Example 1 Part C for 2.5 hoursto give crude product which was purified on an Isco 4 g silica cartridgeeluting with ethyl acetate/hexane (0% to 20%) to give the titlecompound.

Part E. Preparation ofN-((6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(5-methylfuran-2-yl)phenyl)-1H-inden-3-yl)methyl)methanesulfonamide

The product from Part D (0.015 g, 0.024 mmol) was reacted in the samemanner as Example 3 Part B to give the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 2.38 (s, 3H) 2.96 (s, 3H) 3.29 (s, 3H) 3.47 (s, 2H) 4.19(d, J=4.78 Hz, 2H) 6.26 (d, J=2.94 Hz, 1H) 6.56 (s, 1H) 6.90 (d, J=3.31Hz, 1H) 7.38 (d, J=2.21 Hz, 1H) 7.50 (t, J=6.07 Hz, 1H) 7.58 (d, J=1.10Hz, 2H) 7.74 (d, J=9.56 Hz, 2H) 7.86 (d, J=2.21 Hz, 1H) 11.16 (s, 1H)11.27 (s, 1H).

Example 45 Preparation of(E)-N′-((3′-tert-butyl-5′-(2-(1,1-dioxidoisothiazolidin-2-yl))-2′methoxybiphenyl-4-yl)methylene)methanesulfonylhydrazide

Part A. Preparation of tert-butyl 3-bromo-5-tert-butyl4-methoxyphenylcarbamate

To a flask containing N-(3-bromo-5-tert-butyl-4-methoxyphenyl)acetamide(2.2 g, 7.33 mmol) was added 6 N HCl (24.4 mL, 147 mmol) and thesolution was heated at reflux for 2 hours. The cooled solution wasbasified carefully with saturated NaHCO₃ solution, extracted with ethylacetate, the organic extracts combined, washed with brine, dried(Na₂SO₄), filtered and concentrated in vacuo to give a residue which wasdissolved in tetrahydrofuran (36.6 mL) and di-tert-butyl dicarbonate(1.87 mL, 8.1 mmol) was added and refluxed for 3 hours, cooled andsolvent removed in vacuo to give crude product which was purified bysilica gel flash chromatography eluting with 30% ethyl acetate/hexane togive the title compound.

Part B. Preparation of2-(3-bromo-5-tert-butyl-4-methoxyphenyl)isothiazolidine 1,1-dioxide

To a solution of product from Part A (442 mg, 1.2 mmol) indichloromethane (5 mL) was added trifluoroacetic acid (5 mL) andstirring was continued at room temperature for 1 hour, solvent wasremoved in vacuo and the crude product was dissolved in 1:1 ethylacetate/saturated NaHCO₃. The phases were separated and the aqueousphase was extracted with ethyl acetate, the organic extracts were washedwith brine, dried (Na₂SO₄), filtered and concentrated in vacuo. Benzene(2.5 mL) was added followed by pyridine (0.37 mL, 4.6 mmol) and3-chloropropane-1-sulfonyl chloride (0.15 mL, 1.2 mmol) and stirring wascontinued at room temperature for 6 hours. Solvent was removed in vacuoand the crude residue was placed under vacuum for 1 hour, 2 M NaOH (3.0mL, 6 mmol) was added and the solution was heated at 45° C. for 18hours. The cooled solution was diluted with H₂O, extracted with ethylacetate, the organic extracts were washed with brine, dried (Na₂SO₄),filtered and concentrated in vacuo to give crude product which waspurified by silica gel flash chromatography eluting with 25% ethylacetate/hexane to give the title compound.

Part C. Preparation of3′-tert-butyl-5′-(2-(1,1-dioxidoisothiazolidin-2-yl))-2′-methoxybiphenyl-4-carbaldehyde

To a microwave tube containing ethanol (1 mL) and toluene (1 mL) wasadded product from Part B (65 mg, 0.18 mmol), 4-formylphenylboronic acid(35 mg, 0.23 mmol), and 1 M Na₂CO₃ (0.18 mL, 0.18 mmol) and the solutionwas de-gassed with N₂ for 15 minutes. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (7.3mg, 9 mmol) was added and the solution was de-gassed another 5 minutes,the tube sealed and heated in the microwave at 100° C. for 30 minutes,cooled and diluted with 1:1 ethyl acetate/H₂O and filtered throughdiatomaceous earth. The phases were separated and the aqueous phase wasextracted with ethyl acetate, the organic extracts were washed withbrine, dried (Na₂SO₄), filtered and concentrated in vacuo to give thetitle compound.

Part D. Preparation of(E)-N′-((3′-tert-butyl-5′-(2-(1,1-dioxidoisothiazolidin-2-yl))-2′methoxybiphenyl-4-yl)methylene)methanesulfonylhydrazide

To a solution of the product from Part C (45 mg, 0.12 mmol) in methanol(0.5 mL) was added methanesulfonohydrazide (13 mg, 0.12 mmol) with rapidstirring. After stirring at 35° C. for 1 hour, the solvent was removedin vacuo, and the crude product was suspended in diethyl ether,filtered, and the resulting solid collected by filtration to give thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.39 (s, 9H) 2.31-2.45(m, 2H), 3.09 (s, 3H), 3.21 (s, 3H), 3.48 (t, J=7.54 Hz, 2H), 3.76 (t,J=6.43 Hz, 2H), 7.02 (d, J=2.57 Hz, 1H), 7.18 (d, J=2.94 Hz, 1H), 7.58(d, J=8.46 Hz, 2H), 7.77 (d, J=8.46 Hz, 2H), 8.05 (s, 1H), 11.11 (s,1H).

Example 46 Preparation ofN-(6-(3-tert-butyl-5-(2-(1,1-dioxidoisothiazolidin-2-yl))-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide

N-(6-(3-tert-butyl-5-(2-(1,1-dioxidoisothiazolidin-2-yl))-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide

The product from Example 45 Part B (52 mg, 0.14 mmol) andN-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-yl)methanesulfonamide(64.8 mg, 0.19 mmol) were reacted in the same manner as Example 43 PartC to give crude product which was purified by silica gel flashchromatography eluting with ethyl acetate/hexane (20% to 30%) to givethe title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.41 (s, 9H),2.30-2.45 (m, 2H), 3.08 (s, 3H), 3.18 (s, 3H), 3.49 (t, J=7.54 Hz, 2H),3.77 (t, J=6.62 Hz, 2H), 7.15 (dd, J=29.78, 2.57 Hz, 2H), 7.42 (dd,J=8.64, 2.02 Hz, 1H), 7.61-7.76 (m, 2H), 7.86-8.04 (m, 3H), 10.03 (s,1H).

Example 47 Preparation ofN-(3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido)naphthalen-2-yl)phenyl)acetamide

N-(3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido)naphthalen-2-yl)phenyl)acetamide

N-(3-bromo-5-tert-butyl-4-methoxyphenyl)acetamide (24 mg, 0.08 mmol) andN-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-yl)methanesulfonamide(64 mg, 0.18 mmol), were reacted in the same manner as Example 43 PartC, heating in an oil bath at 90° C. for 18 hours to give crude productwhich was purified on an Isco 4 g silica cartridge eluting with 5%methanol/chloroform to give the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.39 (s, 9H), 2.02 (s, 3H), 3.06 (s, 3H), 3.16 (s, 3H),7.34-7.76 (m, 5H), 7.84-8.00 (m, 3H), 9.91 (s, 1H).

Example 48 Preparation of5-(3-bromo-4-methoxy-5-(trifluoromethyl)phenyl)pyrimidine-2,4(1H,3H)-dione

Part A. Preparation of 4-iodo-2-(trifluoromethyl)phenol

A solution of 2-trifluoromethylphenol (10 g, 61.7 mmol) in methanol (125mL) at room temperature was treated with sodium hydroxide (13.87 g, 93mmol) and stirred until homogeneous. The mixture was cooled in an icebath and sodium iodide (2.96 g, 74 mmol) was added portionwise followedby the addition of 10% sodium hypochlorite (84 mL, 136 mmol) dropwise,dividing these reagents into 3 portions and adding them sequentiallyover 30 minutes. The solution was then adjusted to pH 1 by dropwiseaddition of concentrated hydrochloric acid and poured into brine. Theproduct was extracted into ethyl acetate, concentrated in vacuo andpurified by silica gel flash chromatography eluting with ethylacetate/hexane (0% to 5%) to give the title compound.

Part B. Preparation of 2-bromo-4-iodo-6-(trifluoromethyl)phenol

A solution of the product from Part A (15.9 g, 55.2 mmol) in chloroform(230 mL) at room temperature was treated with bromohydantoin (8.68 g,30.4 mmol) and stirred for 1.5 hours. The reaction solution was washedwith water, concentrated in vacuo and purified by silica gel flashchromatography eluting with dichloromethane/hexane (50% to 100%) to givethe title compound.

Part C. Preparation of1-bromo-5-iodo-2-methoxy-3-(trifluoromethyl)benzene

The product from Part B (12.12 g, 33.0 mmol) was reacted in the samemanner as Example 1 Part A at 60° C. for 7 hours to give crude productwhich was purified by silica gel flash chromatography eluting with ethylacetate/hexane (0% to 2%) to give the title compound.

Part D. Preparation of5-(3-bromo-4-methoxy-5-(trifluoromethyl)phenyl)-2,4-di-tert-butoxypyrimidine

The product from Part C (0.40 g, 1.05 mmol) and the product from Example28 Part B (0.338 g, 1.26 mmol) were reacted in the same manner asExample 1 Part B to give crude product which was purified by silica gelflash chromatography eluting with ethyl acetate/hexane (2% to 5%) togive the title compound.

Part E. Preparation of5-(3-bromo-4-methoxy-5-(trifluoromethyl)phenyl)pyrimidine-2,4(1H,3H)-dione

A solution of the product from Part D (0.027 g, 0.058 mmol) indichloromethane (1 mL) at room temperature was treated with 4 M HCl indioxane (1 mL) for 2 hours. The precipitate was filtered and dried togive the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.88 (s, 3H)7.91 (s, 1H) 7.93 (d, J=2.21 Hz, 1H) 8.17 (d, J=2.21 Hz, 1H) 11.37 (s,2H).

Example 49 Preparation ofN-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(trifluoromethyl)phenyl)naphthalen-2-yl)methanesulfonamide

Part A. Preparation ofN-(6-(5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxy-3-(trifluoromethyl)phenyl)naphthalen-2-yl)methanesulfonamide

A solution of the product from Example 48 Part D (0.075 g, 0.16 mmol) intoluene (1 mL) and ethanol (1 mL) in a tube was treated withN-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-yl)methanesulfonamide(0.060 g, 0.17 mmol), 1 μl sodium carbonate solution (0.24 mL, 0.24mmol), and tetrakis(triphenylphosphine)palladium(0) (0.0055 g, 0.0047mmol), then nitrogen was bubbled through the solution for 15 minutesbefore the tube was sealed and heated to 90° C. for 2 hours. Thesolution was cooled, poured into 0.25 M HCl solution, extracted intoethyl acetate, concentrated in vacuo and purified by silica gel flashchromatography eluting with methanol/dichloromethane (0% to 2%) to givethe title compound.

Part B. Preparation ofN-(6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(trifluoromethyl)phenyl)naphthalen-2-yl)methanesulfonamide

A solution of the product from Part A (0.62 g, 0.10 mmol) was reacted inthe same manner as Example 2 Part C for 1 hour to give the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.09 (s, 3H) 3.32 (s, 3H) 7.43(dd, J=8.82, 2.21 Hz, 1H) 7.74-7.78 (m, 2H) 7.91-8.02 (m, 5H) 8.13 (s,1H) 10.07 (s, 1H) 11.31 (dd, J=6.25, 1.10 Hz, 1H) 11.36 (d, J=1.47 Hz,1H).

Example 50 Preparation of(E)-N-(4-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(trifluoromethyl)styryl)phenyl)methanesulfonamide

Part A. Preparation of(E)-N-(4-(5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxy-3-(trifluoromethyl)styryl)phenyl)methanesulfonamide

A solution of the product from Example 48 Part D (0.075 g, 0.16 mmol)and (E)-4-(methylsulfonamido)styryl boronic acid (0.042 g, 0.17 mmol)were reacted in the same manner as Example 49 Part A to give crudeproduct which was purified by silica gel flash chromatography elutingwith methanol/dichloromethane (0% to 2%) to give the title compound.

Part B. Preparation of(E)-N-(4-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(trifluoromethyl)styryl)phenyl)methanesulfonamide

A solution of the product from Part A (0.64 g, 0.11 mmol) was reacted inthe same manner as Example 2 Part C for 1 hour to give the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.03 (s, 3H) 3.81 (s, 3H)7.21-7.43 (m, 4H) 7.65 (d, J=8.46 Hz, 2H) 7.81 (d, J=2.21 Hz, 1H) 7.89(d, J=5.88 Hz, 1H) 8.13 (d, J=1.84 Hz, 1H) 9.90 (s, 1H) 11.33 (d, J=5.88Hz, 1H) 11.36 (d, J=1.10 Hz, 1H).

Example 51 Preparation ofN-((6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)methyl)methanesulfonamide

Part A. Preparation ofN-((6-(5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxy-3-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)methyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide

A solution of the product from Example 48 Part D (0.095 g, 0.199 mmol)andN-(2,4-dimethoxybenzyl)-N-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-3-yl)methyl)methanesulfonamide(0.113 g, 0.22 mmol) were reacted in the same manner as Example 49 PartA at 85° C. to give crude product which was purified by silica gel flashchromatography eluting with ethyl acetate/hexane (0% to 20%) to give thetitle compound.

Part B. Preparation ofN-((6-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-methoxy-3-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)methyl)methanesulfonamide

A solution of the product from Part A (0.97 g, 0.12 mmol) was reacted inthe same manner as Example 2 Part C for 1 hour to give the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.95 (s, 3H) 3.32 (s, 3H) 4.45(d, J=5.88 Hz, 2H) 7.64 (t, J=6.07 Hz, 1H) 7.70 (dd, J=8.46, 1.47 Hz,1H) 7.73 (s, 1H) 7.89 (d, J=2.21 Hz, 1H) 7.93 (dd, J=4.04, 1.84 Hz, 2H)8.05 (d, J=8.46 Hz, 1H) 8.26 (d, J=1.47 Hz, 1H) 11.32 (d, J=5.88 Hz, 1H)11.36 (s, 1H).

Example 52 Preparation ofN-((6-(2-methoxy-5-(1-(methylsulfonyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-(trifluoromethyl)phenyl)-1H-inden-3-yl)methyl)methanesulfonamide

Part A. Preparation ofN-((6-(5-(2,4-di-tert-butoxypyrimidin-5-yl)-2-methoxy-3-(trifluoromethyl)phenyl)-1H-inden-3-yl)methyl)methanesulfonamide

A solution of the product from Example 48 Part D (0.080 g, 0.17 mmol)andN-46-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-inden-3-yl)methyl)methanesulfonamide(0.0685 g, 0182 mmol) was reacted in the same manner as Example 49 PartA at 60° C. for 3 hours to give crude product which was purified bysilica gel flash chromatography eluting with ethyl acetate/hexane (0% to20%) to give the title compound.

Part B. Preparation of5-(3-(3-(aminomethyl)-1H-inden-6-yl)-4-methoxy-5-(trifluoromethyl)phenyl)pyrimidine-2,4(1H,3H)-dionehydrochloride

The product from Part A (0.052 g, 0.08 mmol) in dioxane (4 mL) wastreated with 4 μl HCl in dioxane (3 mL) at room temperature for 4 hoursand concentrated in vacuo to give the title compound which is usedimmediately in the next step.

Part C. Preparation ofN-((6-(2-methoxy-5-(1-(methylsulfonyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-(trifluoromethyl)phenyl)-1H-inden-3-yl)methyl)methanesulfonamide

To a solution of the product of Part B (0.037 g, 0.079 mmol) indichloromethane (3 mL) cooled in an ice bath was addeddiisopropylethylamine (0.055 mL, 0.32 mmol) followed by methanesulfonylchloride (0.0068 mL, 0.087 mmol). The ice bath was removed and thesolution was stirred at room temperature for 2 hours with no reactionseen. Another 0.005 μL of methanesulfonyl chloride was added and thesolution was stirred another 1 hour. The solution was poured into 1 μlHCl, extracted into ethyl acetate, concentrated in vacuo and the crudeproduct was purified by silica gel flash chromatography eluting withmethanol/dichloromethane (0% to 5%) to give the title compound. ¹H NMR(300 MHz, DMSO-d₆) δ 2.96 (s, 3H) 3.35 (s, 3H) 3.49 (d, J=1.10 Hz, 2H)3.74 (s, 3H) 4.19 (d, J=4.78 Hz, 2H) 6.59 (s, 1H) 7.50 (t, J=6.07 Hz,1H) 7.54-7.59 (m, 1H) 7.61-7.67 (m, 1H) 7.72 (s, 1H) 7.79 (s, 2H) 8.01(s, 1H) 12.17 (s, 1H).

HCV Polymerase Inhibition Assay

Either two-fold serial dilutions (fractional inhibition assay) or anarrower range of dilutions spanning the IC₅₀ of the inhibitor (tightbinding assay) of the inhibitors were incubated with 20 mM Tris-Cl pH7.4, 2 mM MnCl₂, 1 mM dithiothreitol, 1 mM ethylene diamine tetraaceticacid (EDTA), 60 to 125 μM GTP and 20 to 50 nM Δ21 NS5B (HCV Strain 1B(BK, Genbank accession number M58335, or H77, Genbank accession numberAF011751)) for 15 minutes at room temperature. The reaction wasinitiated by the addition of 20 μM CTP, 20 μM ATP, 1 μM ³H-UTP (10mCi/umol), 5 nM template RNA and 0.1 U/μl RNase inhibitor (RNasin,Promega), and allowed to proceed for 2 to 4 hours at room temperature.Reaction volume was 50 μL. The reaction was terminated by the additionof 1 volume of 4 mM spermine in 10 mM Tris-Cl pH 8.0, 1 mM EDTA. Afterincubation for at least 15 minutes at room temperature, the precipitatedRNA was captured by filtering through a GF/B filter (Millipore) in a 96well format. The filter plate was washed three times with 200 μL, eachof 2 mM spermine, 10 mM Tris-Cl pH 8.0, 1 mM EDTA, and 2 times withethanol. After air-drying, 30 μL, of Microscint 20 scintillationcocktail (Packard) was added to each well, and the retained cpm weredetermined by scintillation counting. IC₅₀ values were calculated by atwo-variable nonlinear regression equation using an uninhibited controland a fully inhibited control sample to determine the minimum andmaximum for the curve. Tight-binding assays were performed on thosecompounds exhibiting IC₅₀ values less than 0.005 μM in the fractionalinhibition assay in order to more precisely measure the IC₅₀ values.Retained cpm were plotted vs. inhibitor concentration and fit toequation 1 using non-linear regression (ref. 1) to obtain the IC₅₀values:

Retained cpm=A[sqrt{(IC₅₀ +I _(t) −E _(t))̂2+4*IC₅₀ *E _(t)}−(IC₅₀ +I_(t) −E _(t))]  (eqn 1)

where A=Vmax[S]/2(Km+[S]); It=total inhibitor concentration and Et=totalactive concentration of enzyme.

Ref. Morrison, J. F. and S. R. Stone. 1985. Approaches to the study andanalysis of the inhibition of enzymes by slow- and tight-bindinginhibitors. Comments Mol. Cell. Biophys. 2: 347-368.

The sequence of the template RNA used was: 5′-GGGCGAAUUG GGCCCUCUAGAUGCAUGCUC GAGCGGCCGC CAGUGUGAUG GAUAUCUGCA GAAUUCGCCC UUGGUGGCUCCAUCUUAGCC CUAGUCACGG CUAGCUGUGA AAGGUCCGUG AGCCGCUUGA CUGCAGAGAGUGCUGAUACU GGCCUCUCUG CAGAUCAAGUC-3′

When tested by the above method, the compounds of this invention inhibitHCV polymerase 1A and/or 1B. The legend in the table below is asfollows: A—IC₅₀≦0.01 uM; B—0.1 uM≧IC₅₀>0.01 uM: C—1 uM≧IC₅₀>0.1 uM: andD—IC₅₀>1 uM; ND—not determined.

TABLE IC₅₀ compound 1a 1b compound 1a 1b 1 C C 2 A A 3 A A 4 A B 5 D D 6A B 7 A B 8 C C 9 A B 10 C D 11 D D 12 B B 13 C C 14 A B 15 A B 16 B B17 D D 18 D D 19 D D 20 D D 21 C D 22 C C 23 C D 24 D D 25 C C 26 B B 27B B 28 A B 29 B B 30 B B 31 D D 32 D D 33 A B 34 A B 35 A A 36 B B 37 AB 38 A B 39 A A 40 A A 41 C C 42 A B 43 A A 44 B B 45 C C 46 B B 47 C D48 D D 49 A B 50 B B 51 A B 52 B B

HCV Polymerase Replicon Assay

Two stable subgenomic replicon cell lines were used for compoundcharacterization in cell culture: one derived from genotype 1a-H77 andone derived from genotype 1b-Con1 (obtained from Apath, LLC, St. Louis,Mo.). All replicon constructs were bicistronic subgenomic repliconssimilar to those described by SCIENCE 285:110-3 (1999). The genotype 1areplicon construct contains NS3—NS5B coding region derived from the H77strain of HCV (1a-H77) (J. VIROL. 77:3181-90 (2003)). The replicon alsohas a firefly luciferase reporter and a neomycin phosphotransferase(Neo) selectable marker. These two coding regions, separated by the FMDV2a protease, comprise the first cistron of the bicistronic repliconconstruct, with the second cistron containing the NS3—NS5B coding regionwith addition of adaptive mutations E1202G, K1691R, K2040R and S2204I.The 1b-Con1 replicon construct is identical to the 1a-H77 replicon,except that the NS3—NS5B coding region was derived from the 1b-Con1strain, and the adaptive mutations are E1202G, T1280I and S2204I.Replicon cell lines were maintained in Dulbecco's modified Eagles medium(DMEM) containing 10% (v/v) fetal bovine serum (FBS), 100 IU/mLpenicillin, 100 mg/mL streptomycin (Invitrogen), and 200 mg/mL G418(Invitrogen).

The inhibitory effects of compounds on HCV replication were determinedby measuring activity of the luciferase reporter gene. Briefly,replicon-containing cells were seeded into 96 well plates at a densityof 5000 cells per well in 100 μL DMEM containing 5% FBS. 16-24 hourslater, the compounds were diluted in dimethyl sulfoxide (DMSO) togenerate a 200× stock in a series of eight half-log dilutions. Thedilution series was then further diluted 100-fold in the mediumcontaining 5% FBS. Medium with the inhibitor was added to the overnightcell culture plates already containing 100 μL of DMEM with 5% FBS. Inassays measuring inhibitory activity in the presence of human plasma,the medium from the overnight cell culture plates was replaced with DMEMcontaining 40% human plasma and 5% FBS. The cells were incubated forthree days in the tissue culture incubators and were then lysed for RNAextraction. For the luciferase assay, 30 μL of Passive Lysis buffer(Promega) was added to each well, and then the plates were incubated for15 minutes with rocking to lyse the cells. Luciferin solution (50 to 100μL, Promega) was added to each well, and luciferase activity wasmeasured with a Victor II luminometer (Perkin-Elmer). The percentinhibition of HC RNA replication was calculated for each compoundconcentration and the EC₅₀ value was calculated using nonlinearregression curve fitting to the 4-parameter logistic equation andGraphPad Prism 4 software.

When tested by the above method, the compounds of this invention inhibitHCV polymerase 1A and/or 1B. The legend in the table below is asfollows: A—EC₅₀≦0.01 μM; B—0.1 μM≧EC₅₀>0.01 μM; C—1 μM≧EC₅₀>0.1 μM; andD—EC₅₀>1 μM; ND—not determined

TABLE EC₅₀ compound 1a 1b compound 1a 1b 1 ND ND 2 B A 3 A A 4 A A 5 D D6 C A 7 B A 8 C B 9 A A 10 C D 11 ND D 12 C C 13 D D 14 C B 15 C B 16 CC 17 ND ND 18 ND ND 19 ND ND 20 ND ND 21 C C 22 C C 23 D D 24 ND ND 25 DD 26 B A 27 C B 28 A A 29 C B 30 C B 31 ND ND 32 ND ND 33 C B 34 C B 35B A 36 C C 37 C B 38 C B 39 B A 40 C B 41 D D 42 B A 43 C B 44 C B 45 DC 46 C B 47 D C 48 D D 49 B A 50 C B 51 C B 52 C A

All references (patent and non-patent) cited above are incorporated byreference into this patent application. The discussion of thosereferences is intended merely to summarize the assertions made by theirauthors. No admission is made that any reference (or a portion of anyreference) is relevant prior art (or prior art at all). Applicantsreserve the right to challenge the accuracy and pertinence of the citedreferences.

We claim:
 1. A compound or salt thereof, wherein: the compoundcorresponds in structure to formula (I):

R¹ is selected from the group consisting of:

arylcarbonyl, and heteroarylcarbonyl;

is selected from the group consisting of single carbon-carbon bond anddouble carbon-carbon bond; R¹¹, R¹², R¹³, and R¹⁴ are independentlyselected from the group consisting of hydrogen, methyl, andnitrogen-protecting group; R⁹ is halo; R¹⁰ is halo; n is selected fromthe group consisting of 1, 2, and 3; R¹⁵ is selected from the groupconsisting of hydrogen, amino, and nitrogen-protecting group substitutedamino; m is selected from the group consisting of 0, 1, 2, and 3; R¹⁶ isselected from the group consisting of hydrogen, aryl, alkyl, andalkyloxycarbonyl; R² is selected from the group consisting of halo,alkyl, alkenyl, alkynyl, nitro, cyano, azido, alkyloxy, alkenyloxy,alkynyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl,carbocyclyl, and heterocyclyl, wherein: (a) the amino, aminocarbonyl,and aminosulfonyl optionally are substituted with: (1) one or twosubstituents independently selected from the group consisting of alkyl,alkenyl, alkynyl, and alkylsulfonyl, or (2) two substituents that,together with the amino nitrogen, form a single-ring heterocyclyl, and(b) the alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, andalkylsulfonyl, optionally are substituted with one or more substituentsindependently selected from the group consisting of halo, oxo, nitro,cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocyclyl, andheterocyclyl, wherein: the amino optionally is substituted with: (1) oneor two substituents independently selected from the group consisting ofalkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl, alkyloxycarbonyl,carbocyclyl, heterocyclyl, carbocyclylalkyl, and heterocyclylalkyl, or(2) two substituents that, together with the amino nitrogen, form asingle-ring heterocyclyl, and (c) the carbocyclyl and heterocyclyloptionally are substituted with up to three substituents independentlyselected from the group consisting of alkyl, alkenyl, alkynyl, halo,oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl,carbocyclyl, and heterocyclyl, wherein: the amino optionally issubstituted with: (1) one or two substituents independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonyl,alkylsulfonyl, alkyloxycarbonyl, carbocyclyl, heterocyclyl,carbocyclylalkyl, and heterocyclylalkyl, or (2) two substituents that,together with the amino nitrogen, form a single-ring heterocyclyl; R³ isselected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl,alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy, amino,carbocyclylsulfonyloxy, haloalkylsulfonyloxy, and halo; as to L and R⁴:L is a bond, and R⁴ is selected from the group consisting ofC₅-C₆-carbocyclyl, fused 2-ring carbocyclyl and fused 2-ringheterocyclyl, wherein each such substituent optionally is substitutedwith one or more substituents independently selected from the groupconsisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), and R^(K), or Lis selected from the group consisting of C(R^(A))═C(R^(B)), C≡C,C(O)N(R^(C)), N(R^(D))C(O), C₁-C₂-alkylene, CH₂O, OCH₂,cyclopropyl-1,2-ene, CH₂N(R^(L)), N(R^(M))CH₂, C(O)CH₂, and CH₂C(O), andR⁴ is selected from the group consisting of C₅-C₆-carbocyclyl and5-6-membered heterocyclyl, wherein each such substituent optionally issubstituted with one or more substituents independently selected fromthe group consisting of R^(E), R^(F), R^(G), R^(H), R^(I), R^(J), andR^(K); R^(A), R^(B), R^(L), and R^(M) are independently selected fromthe group consisting of hydrogen, C₁-C₆-alkyl, C₁-C₆-alkyloxy,C₃-C₈-cycloalkyl, and halo, wherein: the C₁-C₆-alkyl optionally issubstituted with one or more substituents independently selected fromthe group consisting of carboxy, halo, hydroxy, nitro, oxo, amino,cyano, alkyloxycarbonyl, alkylcarbonyloxy, alkyloxy, carbocyclyl, andheterocyclyl; R^(C) is selected from the group consisting of hydrogenand alkyl; R^(D) is selected from the group consisting of hydrogen andalkyl; each R^(E) is independently selected from the group consisting ofhalo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido, andaldehydro, wherein: the amino optionally is substituted with one or twosubstituents independently selected from the group consisting of alkyl,alkenyl, and alkynyl; each R^(F) is independently selected from thegroup consisting of alkyl, alkenyl, and alkynyl, wherein: each suchsubstituent optionally is substituted with one or more substituentsindependently selected from the group consisting of carboxy, hydroxy,halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl,alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy,alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, andaminocarbonyl, wherein: the amino, imino, aminosulfonyl, aminocarbonyl,carbocyclyl, and heterocyclyl optionally are substituted with one or twosubstituents independently selected from the group consisting of alkyl,alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl,alkylsulfonylamino, hydroxy, and alkyloxy, wherein: amino portion of thealkylsulfonylamino optionally is substituted with a substituent selectedfrom the group consisting of alkyl, alkenyl, and alkynyl; each R^(G) isindependently selected from the group consisting of carbocyclyl andheterocyclyl, wherein: each such substituent optionally is substitutedwith one or more substituents independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, halo, amino,nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl,alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy,alkynylcarbonyloxy, alkyloxy, alkenyloxy, alkynyloxy, carbocyclyl,heterocyclyl, cyano, and aminocarbonyl, wherein: the amino,aminosulfonyl, and aminocarbonyl optionally are substituted with one ortwo substituents independently selected from the group consisting ofalkyl, alkenyl, alkynyl, alkylsulfonyl, alkenylsulfonyl, andalkynylsulfonyl; each R^(H) is independently selected from the groupconsisting of alkyloxy, alkenyloxy, alkynyloxy, alkylsulfonyloxy,alkenylsulfonyloxy, and alkynylsulfonyloxy, wherein: each suchsubstituent optionally is substituted with one or more substituentsindependently selected from the group consisting of carboxy, hydroxy,halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl,alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy,alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl,wherein: the amino, aminosulfonyl, and aminocarbonyl optionally aresubstituted with one or two substituents independently selected from thegroup consisting of alkyl, alkenyl, alkynyl, alkylsulfonyl,alkenylsulfonyl, and alkynylsulfonyl; each R^(I) is independentlyselected from the group consisting of alkylcarbonyl, alkenylcarbonyl,alkynylcarbonyl, aminocarbonyl, alkyloxycarbonyl, carbocyclylcarbonyl,and heterocyclylcarbonyl, wherein: (a) the alkylcarbonyl,alkenylcarbonyl, and alkynylcarbonyl optionally are substituted with oneor more substituents independently selected from the group consisting ofcarboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl,alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy,alkenyloxy, alkynyloxy, carbocyclyl, heterocyclyl, cyano, andaminocarbonyl, and (b) the aminocarbonyl optionally is substituted withone or two substituents independently selected from the group consistingof alkyl, alkenyl, alkynyl, alkyloxyalkyl, carbocyclyl, heterocyclyl,alkylsulfonyl, and alkylsulfonylamino, wherein: the carbocyclyl andheterocyclyl optionally are substituted with one or two substituentsindependently selected from the group consisting of halo, alkyl, andoxo; each R^(J) is independently selected from the group consisting ofcarbocyclylsulfonylamino, heterocyclylsulfonylamino, alkylcarbonylamino,alkenylcarbonylamino, alkynylcarbonylamino, alkyloxycarbonylamino,alkenyloxycarbonylamino, alkynyloxycarbonylamino, alkylsulfonylamino,alkenylsulfonylamino, alkynylsulfonylamino, aminocarbonylamino,alkyloxycarbonylaminoimino, alkylsulfonylaminoimino,alkenylsulfonylaminoimino, and alkynylsulfonylaminoimino, wherein: (a)the amino portion of such substituents optionally is substituted with asubstituent independently selected from the group consisting ofcarbocyclylalkyl, heterocyclylalkyl, alkylcarbonyloxy,aminocarbonylalkyl, alkyl, alkenyl, alkynyl, alkylcarbonyl,alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl,alkyloxyalkyloxycarbonyl, alkylcarbonyloxyalkyl, and alkylsulfonyl,wherein: (1) the carbocyclyl portion of the carbocyclylalkyl and theheterocyclyl portion of the heterocyclylalkyl optionally are substitutedwith one or more substituents independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkyloxy,alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, oxo, and amino, and(2) the amino portion of the aminocarbonylalkyl optionally issubstituted with one or two substituents independently selected from thegroup consisting of alkyl, alkenyl, and alkynyl, (b) the alkyl, alkenyl,and alkynyl portion of such substituents optionally is substituted withone or more substituents independently selected from the groupconsisting of carboxy, halo, oxo, amino, alkyloxycarbonyl,alkylcarbonyloxy, hydroxy, alkyloxy, carbocyclyl, heterocyclyl, andcyano, wherein: the amino optionally is substituted with one or twosubstituents independently selected from the group consisting of alkyl,alkenyl, alkynyl, alkyloxy, alkenyloxy, and alkynyloxy, wherein: thealkyl optionally is substituted with one or more hydroxy; (c) thecarbocyclyl and heterocyclyl portions of such substituents optionallyare substituted with one or more substituents independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, carboxy, hydroxy,alkyloxy, alkenyloxy, alkynyloxy, halo, nitro, cyano, azido, and amino,wherein: the amino optionally is substituted with one or twosubstituents independently selected from the group consisting of alkyl,alkenyl, and alkynyl; and each R^(K) is independently selected from thegroup consisting of amino sulfonyl, alkylsulfonyl, alkenylsulfonyl, andalkynylsulfonyl, wherein: (a) the alkylsulfonyl, alkenylsulfonyl, andalkynylsulfonyl optionally are substituted with one or more substituentsindependently selected from the group consisting of carboxy, hydroxy,halo, amino, nitro, azido, oxo, aminosulfonyl, alkyloxycarbonyl,alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxy, alkenyloxy,alkynyloxy, carbocyclyl, heterocyclyl, cyano, and aminocarbonyl,wherein: the amino, aminosulfonyl, and aminocarbonyl optionally aresubstituted with one or two substituents independently selected from thegroup consisting of alkyl, alkenyl, and alkynyl; and (b) theaminosulfonyl optionally is substituted with one or two substituentsindependently selected from the group consisting of alkyl, alkenyl, andalkynyl.
 2. (canceled)
 3. The compound or salt of claim 1, wherein R⁵ isselected from the group consisting of hydrogen and methyl. 4-5.(canceled)
 6. The compound or salt of claim 1, wherein R¹ is


7. The compound or salt of claim 6, wherein m is
 0. 8. The compound orsalt of claim 1, wherein m is
 1. 9. The compound or salt of claim 6,wherein m is
 2. 10. The compound or salt of claim 6, wherein m is
 3. 11.The compound or salt of claim 6, wherein R¹⁶ is hydrogen.
 12. Thecompound or salt of claim 6, wherein R¹⁶ is phenyl.
 13. The compound orsalt of claim 6, wherein R¹⁶ is C₁-C₃-alkyl.
 14. The compound or salt ofclaim 6, wherein R¹⁶ is C₁-C₃-alkyloxy-carbonyl.
 15. The compound orsalt of claim 1, wherein R² is selected from the group consisting ofC₁-C₄-alkyl, C₃-C₆-carbocyclyl, and 5-6-membered heterocyclyl, wherein:(a) the C₁-C₄-alkyl optionally is substituted with up to threesubstituents independently selected from the group consisting of halo,oxo, hydroxy, alkyloxy, and trimethylsilyl, and (b) theC₃-C₆-carbocyclyl and 5-6-membered heterocyclyl optionally aresubstituted with one or two substituents independently selected from thegroup consisting of alkyl, halo, and alkylsulfonylamino.
 16. Thecompound or salt of claim 1, wherein R² is selected from the groupconsisting of halo, alkyl, and alkyloxy.
 17. The compound or salt ofclaim 1, wherein R² is selected from the group consisting of tert-butyl,perfluoroethyl, trifluoromethyl, and 5-6-membered heterocyclyloptionally substituted with methyl.
 18. The compound or salt of claim 1,wherein R² is selected from the group consisting of furanyl, pyrazolyl,and thiophenyl, wherein each such substituent optionally is substitutedwith methyl.
 19. The compound or salt of claim 1, wherein R³ is selectedfrom the group consisting of hydrogen, hydroxy, C₁-C₃-alkenyl,C₁-C₃-alkyl, alkyloxy, amino, and halo.
 20. The compound or salt ofclaim 1, wherein R³ is selected from the group consisting of hydrogen,hydroxy, and methoxy.
 21. The compound or salt of claim 1, wherein L isa bond.
 22. The compound or salt of claim 1, wherein: L is a bond; andR⁴ is selected from the group consisting of fused 2-ring heterocyclyland fused 2-ring carbocyclyl, wherein each such substituent issubstituted with one, two, or three substituents independently selectedfrom the group consisting of R^(E), R^(F), and R^(J).
 23. The compoundor salt of claim 1, wherein: L is a bond; R⁴ is a fused 2-ringcarbocyclyl selected from the group consisting of naphthalenyl,dihydronaphthalenyl, tetrahydronaphthalenyl, hexahydronaphthalenyl,octahydronaphthalenyl, decahydronaphthalenyl, indenyl, dihydroindenyl,hexahydroindenyl, octahydroindenyl, pentalenyl, octahydropentalenyl, andhexahydropentalenyl, wherein each such substituent is substituted with asubstituent selected from the group consisting of R^(F) and R^(J); R^(E)is alkylsulfonylaminoalkyl; and R^(J) is alkylsulfonylamino.
 24. Thecompound or salt of claim 1, wherein: L is a bond; R⁴ is a fused 2-ringcarbocyclyl selected from the group consisting of naphthalenyl, indenyl,and dihydroindenyl, wherein each such substituent is substituted with asubstituent selected from the group consisting of R^(F) and R^(J); R^(F)is alkylsulfonylaminoalkyl; and R^(J) is alkylsulfonylamino.
 25. Acompound or salt thereof, wherein the compound is selected from thegroup consisting ofN-(6-(3-tert-butyl-2-methoxy-5-(1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl)naphthalen-2-yl)methanesulfonamide;N-(6-(3-tert-butyl-2-methoxy-5-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)naphthalen-2-yl)methanesulfonamide;N-(6-(3-tert-butyl-2-methoxy-5-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)naphthalen-2-yl)methanesulfonamide;N-(6-5-tert-butyl-2′,4′-difluoro)-4-methoxybiphenyl-3-yl)naphthalen-2-yl)methanesulfonamide;N-(6-(3-tert-butyl-2-methoxy-5-ureidophenyl)naphthalen-2-yl)methanesulfonamide;N-(6-(3-tert-butyl-5-(2-hydroxy-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide;N-(6-(3-tert-butyl-5-(2,4-dioxoimidazolidin-1-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide;N-(6-(3-tert-butyl-2-methoxy-5-(3-phenylureido)phenyl)naphthalen-2-yl)methanesulfonamide;N-(6-(3-tert-butyl-5-(3-isopropylureido)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide; tert-butyl2-(3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido)naphthalen-2-yl)phenylamino)-2-oxoethylcarbamate;2-amino-N-(3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido)naphthalen-2-yl)phenyl)acetamide; ethyl3-(3-(3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido)naphthalen-2-yl)phenyl)ureido)propanoate;N-(6-(3-tert-butyl-5-(3-ethylureido)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide; tert-butyl3-(3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido)naphthalen-2-yl)phenylamino)-3-oxopropylcarbamate;3-amino-N-(3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido)naphthalen-2-yl)phenyl)propanamide;N-(6-(3-tert-butyl-2-methoxy-5-(2-oxooxazolidin-3-yl)phenyl)naphthalen-2-yl)methanesulfonamide;N-(6-(3-tert-butyl-2-methoxy-5-(2-oxotetrahydropyrimidin-1(2H)-yl)phenyl)naphthalen-2-yl)methanesulfonamide;N-(6-(3-tert-butyl-2-methoxy-5-(2-oxoimidazolidin-1-yl)phenyl)naphthalen-2-yl)methanesulfonamide;N-(6-(3-tert-butyl-2-methoxy-5-(2-oxopyrrolidin-1-yl)phenyl)naphthalen-2-yl)methanesulfonamide;N-(6-(3-tert-butyl-2-methoxy-5-(2-oxopyridin-1(2H)-yl)phenyl)naphthalen-2-yl)methanesulfonamide;N-(6-(5-benzoyl-3-tert-butyl-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide;(E)-N-(4-(5-benzoyl-3-tert-butyl-2-methoxystyryl)phenyl)methanesulfonamide;(E)-N′-((3′-tert-butyl-5′-(2-(1,1-dioxidoisothiazolidin-2-yl))-2′methoxybiphenyl-4-yl)methylene)methanesulfonylhydrazide;N-(6-(3-tert-butyl-5-(2-(1,1-dioxidoisothiazolidin-2-yl))-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide;and N-(3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido)naphthalen-2-yl)phenyl)acetamide.
 26. A pharmaceutical compositioncomprising one or more compounds and/or salts recited in claim 1 and oneor more excipients.
 27. The pharmaceutical composition of claim 26,wherein the pharmaceutical composition further comprises one or moreadditional therapeutic agents.
 28. A method for inhibiting replicationof a ribonucleic acid (RNA) virus, wherein the method comprises exposingthe virus to one or more compounds and/or salts recited in claim
 1. 29.The method of claim 28, wherein the RNA virus is hepatitis C virus(HCV).
 30. A method for treating hepatitis C in a mammal in need of suchtreatment, wherein the method comprises administering to the mammal oneor more compounds and/or salts recited in claim
 1. 31. The method ofclaim 30, wherein the mammal is human.
 32. The method of claim 30,wherein the method further comprises administering to the mammal one ormore additional therapeutic agents.
 33. The method of claim 32, whereinone or more additional therapeutic agents are selected from the groupconsisting of interferon agent, ribavirin, HCV inhibitor, and HIVinhibitor.